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  • 1.
    Ahmad, Irma
    et al.
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Edin, Alicia
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Granvik, Christoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kumm Persson, Lowa
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Tevell, Staffan
    Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Månsson, Emeli
    Centre for Clinical Research, Region Västmanland—Uppsala University, Västmanland Hospital Västerås, Västerås, Sweden.
    Magnuson, Anders
    Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Marklund, Ingela
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering. Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Persson, Ida-Lisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kauppi, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sundh, Josefin
    Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lange, Anna
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Cajander, Sara
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-192023Ingår i: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, artikel-id 1104267Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

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  • 2. Baptista, Marisa A. P.
    et al.
    Keszei, Marton
    Oliveira, Mariana
    Sunahara, Karen K. S.
    Andersson, John
    Dahlberg, Carin I. M.
    Worth, Austen J.
    Lieden, Agne
    Kuo, I-Chun
    Wallin, Robert P. A.
    Snapper, Scott B.
    Eidsmo, Liv
    Scheynius, Annika
    Karlsson, Mikael C. I.
    Bouma, Gerben
    Burns, Siobhan O.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Thrasher, Adrian J.
    Nylén, Susanne
    Westerberg, Lisa S.
    Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells2016Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 7, artikel-id 12175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.

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  • 3.
    Beser, Jessica
    et al.
    Public Health Agency of Sweden, Solna, Sweden; European Centre for Disease Prevention and Control (ECDC), European Public Health Microbiology Training Programme (EUPHEM), Solna, Sweden.
    Galanis, Ilias
    Public Health Agency of Sweden, Solna, Sweden.
    Enkirch, Theresa
    Public Health Agency of Sweden, Solna, Sweden.
    Kühlmann Berenzon, Sharon
    Public Health Agency of Sweden, Solna, Sweden.
    van Straten, Edward
    Public Health Agency of Sweden, Solna, Sweden.
    Duracz, Jan
    Public Health Agency of Sweden, Solna, Sweden.
    Rapp, Marie
    Public Health Agency of Sweden, Solna, Sweden.
    Zakikhany, Katherina
    Public Health Agency of Sweden, Solna, Sweden.
    Mansjö, Mikael
    Public Health Agency of Sweden, Solna, Sweden.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Groenheit, Ramona
    Public Health Agency of Sweden, Solna, Sweden.
    Tegmark Wisell, Karin
    Public Health Agency of Sweden, Solna, Sweden.
    Bråve, Andreas
    Public Health Agency of Sweden, Solna, Sweden.
    Seroprevalence of SARS-CoV-2 in Sweden, April 26 to May 9, 20212022Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikel-id 10816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A national point seroprevalence study of SARS-CoV-2 was conducted in Sweden in April–May 2021. In total, 2860 individuals 3 to 90 years old from a probability-based web panel were included. Results showed that an estimated 32.6% of the population in Sweden had detectable levels of antibodies, and among non-vaccinated 20.1% had detectable levels of antibodies. We tested for differences in seroprevalence between age groups and by sex and estimated seroprevalence among previously infected participants by time since reporting.

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  • 4.
    Björsell, Tove
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Sundh, Josefin
    Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lange, Anna
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Tevell, Staffan
    Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Edin, Alicia
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Anestesiologi och intensivvård.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Cajander, Sara
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients2023Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 293, nr 5, s. 600-614Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3–6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods: Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO), was performed 3–6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. Results: Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO, versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO. A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO. Conclusion: Reduced DLCO was the major respiratory impairment 3–6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.

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  • 5.
    Blom, Kim
    et al.
    Public Health Agency of Sweden, Sweden.
    Fjällström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Molnár, Christian
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Familjeläkarna AB, Stockholm, Sweden.
    Åberg, Mikael
    Department of Medical Sciences, Clinical Chemistry and SciLifeLab Affinity Proteomics, Uppsala University, Uppsala, Sweden.
    Vikström, Linnea
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Bennet, Louise
    Clinical Studies Sweden, Forum South, Skåne University Hospital and Department of Clinical Sciences, Lund University, Lund, Sweden.
    Widerström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rasmussen, Gunlög
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Klingström, Jonas
    Department of Biomedical Clinical Sciences, Linköping University, Linköping, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    SARS-CoV-2-related mortality decrease in nursing home residents given multiple COVID-19 boosters2023Ingår i: The Lancet - Infectious diseases, ISSN 1473-3099, E-ISSN 1474-4457, Vol. 23, nr 10, s. e393-e394Artikel i tidskrift (Övrigt vetenskapligt)
  • 6.
    Blom, Kim
    et al.
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden; Public Health Agency of Sweden, Stockholm, Sweden.
    Marking, Ulrika
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Havervall, Sebastian
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Norin, Nina Greilert
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Gordon, Max
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    García, Marina
    Public Health Agency of Sweden, Stockholm, Sweden; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Tecleab, Teghesti
    Public Health Agency of Sweden, Stockholm, Sweden.
    Christ, Wanda
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Phillipson, Mia
    Department of Medical Cell Biology and SciLifeLab, Uppsala University, Uppsala, Sweden.
    Nilsson, Peter
    Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    Mangsbo, Sara
    Department of Pharmacy and SciLifeLab, Uppsala University, Uppsala, Sweden.
    Hober, Sophia
    Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
    Åberg, Mikael
    Department of Medical Sciences, Clinical Chemistry and SciLifeLab, Uppsala University, Uppsala, Sweden.
    Klingström, Jonas
    Public Health Agency of Sweden, Stockholm, Sweden; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Thålin, Charlotte
    Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Immune responses after omicron infection in triple-vaccinated health-care workers with and without previous SARS-CoV-2 infection2022Ingår i: The Lancet - Infectious diseases, ISSN 1473-3099, E-ISSN 1474-4457, Vol. 22, nr 7, s. 943-945Artikel i tidskrift (Refereegranskat)
  • 7.
    Bortz, Robert H.
    et al.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Florez, Catalina
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, NY, United States.
    Laudermilch, Ethan
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Wirchnianski, Ariel S.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lasso, Gorka
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Malonis, Ryan J.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Georgiev, George I.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Vergnolle, Olivia
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Herrera, Natalia G.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Morano, Nicholas C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Campbell, Sean T.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Orner, Erika P.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Mengotto, Amanda
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Dieterle, M. Eugenia
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Fels, J. Maximilian
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Haslwanter, Denise
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Jangra, Rohit K.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Celikgil, Alev
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Kimmel, Duncan
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lee, James H.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Mariano, Margarette C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Nakouzi, Antonio
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Quiroz, Jose
    Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Rivera, Johanna
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Szymczak, Wendy A.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Tong, Karen
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Barnhill, Jason
    Department of Chemistry and Life Science, United States Military Academy at West Point, West Point, NY, United States.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Stein, Daniel T.
    Montefiore Medical Center, NY, Bronx, United States; Division of Endocrinology and Diabetes, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Pirofski, Liise-Anne
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Goldstein, D Yitzchak
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Garforth, Scott J.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Almo, Steven C.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Daily, Johanna P.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, NY, Bronx, United States.
    Prystowsky, Michael B.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Faix, James D.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Fox, Amy S.
    Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States; Montefiore Medical Center, NY, Bronx, United States.
    Weiss, Louis M.
    Montefiore Medical Center, NY, Bronx, United States; Department of Pathology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Lai, Jonathan R.
    Department of Biochemistry, Albert Einstein College of Medicine, NY, Bronx, United States.
    Chandran, Kartik
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, Bronx, United States.
    Single-Dilution COVID-19 Antibody Test with Qualitative and Quantitative Readouts2021Ingår i: mSphere, E-ISSN 2379-5042, Vol. 6, nr 2, artikel-id e00224-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to place an immense burden on societies and health care systems. A key component of COVID-19 control efforts is serological testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior SARS-CoV-2 infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this sensitive test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test make it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.IMPORTANCE Serological surveillance has become an important public health tool during the COVID-19 pandemic. Detection of protective antibodies and seroconversion after SARS-CoV-2 infection or vaccination can help guide patient care plans and public health policies. Serology tests can detect antibodies against past infections; consequently, they can help overcome the shortcomings of molecular tests, which can detect only active infections. This is important, especially when considering that many COVID-19 patients are asymptomatic. In this study, we describe an enzyme-linked immunosorbent assay (ELISA)-based qualitative and quantitative serology test developed to measure IgG and IgA antibodies against the SARS-CoV-2 spike glycoprotein. The test can be deployed using commonly available laboratory reagents and equipment and displays high specificity and sensitivity. Furthermore, we demonstrate that IgG titers in patient samples can be estimated from a single measurement, enabling the assay's use in high-throughput clinical environments.

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  • 8.
    Cable, Jennifer
    et al.
    PhD Science Writer, NY, United States.
    Graham, Barney S.
    Morehouse School of Medicine, GA, Atlanta, United States.
    Koup, Richard A.
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Seder, Robert A.
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Karikó, Katalin
    BioNTech SE, Mainz, Germany.
    Pardi, Norbert
    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Barouch, Dan H.
    Harvard Medical School, MA, Boston, United States.
    Sharma, Bhawna
    Gilead Sciences, CA, Foster City, United States.
    Rauch, Susanne
    CureVac AG, Tübingen, Germany.
    Nachbagauer, Raffael
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, United States; Moderna, MA, Cambridge, United States.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Schotsaert, Michael
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, United States; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, NY, United States.
    Ellebedy, Ali H.
    Department of Pathology and Immunology; Center for Vaccines and Immunity to Microbial Pathogens; and The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA.
    Loré, Karin
    Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Irvine, Darrell J.
    Koch Institute for Integrative Cancer Research; Department of Biological Engineering; and Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA, United States; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, MA, Cambridge, United States.
    Pilkington, Emily
    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Melbourne, Australia; Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Melbourne, Australia.
    Tahtinen, Siri
    Genentech, CA, South San Francisco, United States.
    Thompson, Elizabeth A.
    Department of Medicine, Johns Hopkins University School of Medicine, MD, Baltimore, United States.
    Feraoun, Yanis
    Inserm, Center for Immunology of Viral, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-SaclayFontenay-aux-Roses, CEA, France.
    King, Neil P.
    Department of Biochemistry and Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Saunders, Kevin
    Human Vaccine Institute, Duke University, NC, Durham, United States.
    Alter, Galit
    Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, MA, Cambridge, United States.
    Moin, Syed M.
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Sliepen, Kwinten
    Department of Medical Microbiology, University of Amsterdam, Amsterdam, Netherlands.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Wardemann, Hedda
    Division of B Cell Immunology, German Cancer Research Center, Heidelberg, Germany.
    Pulendran, Bali
    Institute for Immunity, Transplantation and Infection; Department of Pathology; and Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford University, Stanford, California, USA.
    Doria-Rose, Nicole A.
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    He, Wan-Ting
    Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA, United States; Department of Immunology and Microbiology and IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA, United States.
    Juno, Jennifer A.
    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Melbourne, Australia.
    Ataca, Sila
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Wheatley, Adam K.
    Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Melbourne, Australia.
    McLellan, Jason S.
    Department of Molecular Biosciences, University of Texas at Austin, TX, Austin, United States.
    Walker, Laura M.
    Adimab, LLC, NH, United States.
    Lederhofer, Julia
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Lindesmith, Lisa C.
    Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
    Wille, Holger
    Centre for Prions and Protein Folding Diseases and Department of Biochemistry, University of Alberta, AB, Edmonton, Canada.
    Hotez, Peter J.
    Texas Children's Center for Vaccine Development, Departments of Pediatrics and Molecular Virology & Microbiology, National School of Tropical Medicine, Baylor College of Medicine, TX, Houston, United States; James A Baker III Institute for Public Policy, Rice University, TX, Houston, United States; Department of Biology, Baylor University, TX, Waco, United States; Hagler Institute for Advanced Study and Scowcroft Institute of International Affairs, Bush School of Government and Public Service, Texas A&M University, College Station, TX, United States.
    Bekker, Linda-Gail
    Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa.
    Progress in vaccine development for infectious diseases: a Keystone Symposia report2023Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1524, nr 1, s. 65-86Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The COVID-19 pandemic has taught us many things, among the most important of which is that vaccines are one of the cornerstones of public health that help make modern longevity possible. While several different vaccines have been successful at stemming the morbidity and mortality associated with various infectious diseases, many pathogens/diseases remain recalcitrant to the development of effective vaccination. Recent advances in vaccine technology, immunology, structural biology, and other fields may yet yield insight that will address these diseases; they may also help improve societies' preparedness for future pandemics. On June 1-4, 2022, experts in vaccinology from academia, industry, and government convened for the Keystone symposium "Progress in Vaccine Development for Infectious Diseases" to discuss state-of-the-art technologies, recent advancements in understanding vaccine-mediated immunity, and new aspects of antigen design to aid vaccine effectiveness.

  • 9.
    Cagigi, Alberto
    et al.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Yu, Meng
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Österberg, Björn
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Julia
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Falck-Jones, Sara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Vangeti, Sindhu
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Åhlberg, Eric
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Azizmohammadi, Lida
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Warnqvist, Anna
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Falck-Jones, Ryan
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Gubisch, Pia C.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ödemis, Mert
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ghafoor, Farangies
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Eisele, Mona
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Lenart, Klara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bell, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Johansson, Niclas
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Albert, Jan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Microbiology, Karolinska University Laboratory, Karolinska University Hospital Solna, Stockholm, Sweden.
    Sälde, Jörgen
    Närakut SLSO, Karolinska University Hospital Solna, Stockholm, Sweden.
    Pettie, Deleah D.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Murphy, Michael P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Carter, Lauren
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    King, Neil P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Ols, Sebastian
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Forsell, Mattias N.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Färnert, Anna
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Loré, Karin
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Smed-Sörensen, Anna
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination2021Ingår i: JCI Insight, ISSN 2379-3708, Vol. 6, nr 22, artikel-id e151463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.

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  • 10.
    Carrasco, Anna
    et al.
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sjölander, Isabella
    Department of Surgical Sciences, Otorhinolaryngology-Head and Neck Surgery, Uppsala University, Uppsala, Sweden.
    Van Acker, Aline
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Fehrm, Johan
    Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Friberg, Danielle
    Department of Surgical Sciences, Otorhinolaryngology-Head and Neck Surgery, Uppsala University, Uppsala, Sweden.
    Mjösberg, Jenny
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Rao, Anna
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    The Tonsil Lymphocyte Landscape in Pediatric Tonsil Hyperplasia and Obstructive Sleep Apnea2021Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, artikel-id 674080Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naïve CD27-CD21hi B cells and a relative reduction of ILCs. The enrichment of naïve B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.

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  • 11.
    Castro Dopico, Xaquin
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Muschiol, Sandra
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Grinberg, Nastasiya F.
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom.
    Aleman, Soo
    Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden.
    Sheward, Daniel J.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hanke, Leo
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Ahl, Marcus
    Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Sweden.
    Vikström, Linnea
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Coquet, Jonathan M.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    McInerney, Gerald
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Dillner, Joakim
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Bogdanovic, Gordana
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom.
    Murrell, Ben
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Albert, Jan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Wallace, Chris
    Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Probabilistic classification of anti-SARS-CoV-2 antibody responses improves seroprevalence estimates2022Ingår i: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 11, nr 3, artikel-id e1379Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Population-level measures of seropositivity are critical for understanding the epidemiology of an emerging pathogen, yet most antibody tests apply a strict cutoff for seropositivity that is not learnt in a data-driven manner, leading to uncertainty when classifying low-titer responses. To improve upon this, we evaluated cutoff-independent methods for their ability to assign likelihood of SARS-CoV-2 seropositivity to individual samples. Methods: Using robust ELISAs based on SARS-CoV-2 spike (S) and the receptor-binding domain (RBD), we profiled antibody responses in a group of SARS-CoV-2 PCR+ individuals (n = 138). Using these data, we trained probabilistic learners to assign likelihood of seropositivity to test samples of unknown serostatus (n = 5100), identifying a support vector machines-linear discriminant analysis learner (SVM-LDA) suited for this purpose. Results: In the training data from confirmed ancestral SARS-CoV-2 infections, 99% of participants had detectable anti-S and -RBD IgG in the circulation, with titers differing > 1000-fold between persons. In data of otherwise healthy individuals, 7.2% (n = 367) of samples were of uncertain serostatus, with values in the range of 3-6SD from the mean of pre-pandemic negative controls (n = 595). In contrast, SVM-LDA classified 6.4% (n = 328) of test samples as having a high likelihood (> 99% chance) of past infection, 4.5% (n = 230) to have a 50–99% likelihood, and 4.0% (n = 203) to have a 10–49% likelihood. As different probabilistic approaches were more consistent with each other than conventional SD-based methods, such tools allow for more statistically-sound seropositivity estimates in large cohorts. Conclusion: Probabilistic antibody testing frameworks can improve seropositivity estimates in populations with large titer variability.

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  • 12.
    Chernyshev, Mark
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Sakharkar, Mrunal
    NH, United States.
    Connor, Ruth I.
    Department of Pediatrics, Dartmouth-Hitchcock Medical Center, NH, United States.
    Dugan, Haley L.
    NH, United States.
    Sheward, Daniel J.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Rappazzo, C.G.
    NH, United States.
    Stålmarck, Aron
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wright, Peter F.
    Department of Pediatrics, Dartmouth-Hitchcock Medical Center, NH, United States.
    Corcoran, Martin
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Murrell, Ben
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Walker, Laura M.
    NH, United States, MA, Waltham, United States.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 2249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors' personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.

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  • 13.
    Dernstedt, Andy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Leidig, Jana
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Holm, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Kerkman, Priscilla
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Mjösberg, Jenny
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Henriksson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis2021Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, artikel-id 599647Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF(lo) B cells. Consistent with this, a majority of light and dark zone GC B cells were DAF(lo) and susceptible to complement-dependent phagocytosis, as compared with DAF(hi) GC B cells. We could also show that the DAF(hi) GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

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  • 14.
    Forsell, Mattias N. E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Kvastad, Linda
    Sedimbi, Saikiran K.
    Andersson, John
    Karlsson, Mikael C. I.
    Regulation of Subunit-Specific Germinal Center B Cell Responses to the HIV-1 Envelope Glycoproteins by Antibody-Mediated Feedback2017Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 8, artikel-id 738Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.

  • 15.
    Gröning, Remigius
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption2023Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikel-id 1219560Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

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  • 16.
    Gröning, Remigius
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Gardfjäll, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Variable immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis after rituximab treatment interruptionManuskript (preprint) (Övrigt vetenskapligt)
  • 17.
    Holm, Karin
    et al.
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Lundgren, Maria N.
    Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories, Region Skåne, Sweden.
    Kjeldsen-Kragh, Jens
    Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories, Region Skåne, Sweden.
    Ljungquist, Oskar
    Clinical Infection Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden.
    Böttiger, Blenda
    Department of Clinical Microbiology, University and Regional Laboratories, Region Skåne, Sweden.
    Wikén, Christian
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Öberg, Jonas
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Fernström, Nils
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Landin-Olsson, Mona
    Department of Endocrinology, Skåne University Hospital, Lund, Sweden.
    Rasmussen, Magnus
    Department of Infectious diseases, Skåne University Hospital, Lund, Sweden.
    Convalescence plasma treatment of COVID-19: results from a prematurely terminated randomized controlled open-label study in Southern Sweden2021Ingår i: BMC Research Notes, E-ISSN 1756-0500, Vol. 14, nr 1, artikel-id 440Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Convalescent plasma has been tried as therapy for various viral infections. Early observational studies of convalescent plasma treatment for hospitalized COVID-19 patients were promising, but randomized controlled studies were lacking at the time. The objective of this study was to investigate if convalescent plasma is beneficial to hospitalized patients with COVID-19.

    Results: Hospitalized patients with confirmed COVID-19 and an oxygen saturation below 94% were randomized 1:1 to receive convalescent plasma in addition to standard of care or standard of care only. The primary outcome was number of days of oxygen treatment to keep saturation above 93% within 28 days from inclusion. The study was prematurely terminated when thirty-one of 100 intended patients had been included. The median time of oxygen treatment among survivors was 11 days (IQR 6–15) for the convalescent plasma group and 7 days (IQR 5–9) for the standard of care group (p = 0.4, median difference -4). Two patients in the convalescent plasma group and three patients in the standard of care group died (p = 0.64, OR 0.49, 95% CI 0.08–2.79). Thus no significant differences were observed between the groups.

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  • 18.
    Johansson, Emil
    et al.
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Kerkman, Priscilla
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.
    Scharf, Lydia
    Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Lindman, Jacob
    Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Szojka, Zsófia I.
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Månsson, Fredrik
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Biague, Antonio
    National Laboratory for Public Health, Bissau, Guinea-Bissau.
    Medstrand, Patrik
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Norrgren, Hans
    Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Buggert, Marcus
    Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Annika C.
    Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Esbjörnsson, Joakim
    Department of Translational Medicine, Lund University, Malmö, Sweden; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
    Jansson, Marianne
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection2022Ingår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 19, artikel-id 3142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.

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  • 19.
    Kaku, Chengzi I.
    et al.
    United States.
    Bergeron, Alan J.
    Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, United States; Department of Microbiology and Immunology, Dartmouth College, Hanover, United States.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sakharkar, Mrunal
    United States.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Walker, Laura M.
    Waltham, United States.
    Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection2022Ingår i: Science immunology, E-ISSN 2470-9468, Vol. 7, nr 73, artikel-id eabq3511Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses after Omicron/BA.1 infection in messenger RNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of preexisting immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.

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  • 20.
    Kaku, Chengzi I.
    et al.
    Adimab, NH, Lebanon, United States; Thayer School of Engineering, Dartmouth College, NH, Hanover, United States.
    Champney, Elizabeth R.
    Adimab, NH, Lebanon, United States.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Garcia, Marina
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Johnson, Carl E.
    Adimab, NH, Lebanon, United States.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Christ, Wanda
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Sakharkar, Mrunal
    Adimab, NH, Lebanon, United States.
    Ackerman, Margaret E.
    Thayer School of Engineering, Dartmouth College, NH, Hanover, United States; Geisel School of Medicine, Dartmouth College, NH, Hanover, United States.
    Klingström, Jonas
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Walker, Laura M.
    Adimab, NH, Lebanon, United States; Adagio Therapeutics, MA, Waltham, United States.
    Broad anti–SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination2022Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 375, nr 6584, s. 1041-1047Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1: ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–booste participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relativ to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.

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  • 21.
    Kerkman, Priscilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Tadala, Lalitha
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Mittler, Eva
    Dannborg, Mirjam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Sundling, Christopher
    Maleki, Kimia T.
    Tauriainen, Johanna
    Tuiskunen-Bäck, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wigren Byström, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Ocaya, Pauline
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Thunberg, Therese
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Jangra, Rohit K
    Román-Sosa, Gleyder
    Guardado-Calvo, Pablo
    Rey, Feilx A.
    Klingström, Jonas
    Chandran, Kartik
    Puhar, Andrea
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings2021Ingår i: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 10, artikel-id e1313Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms arenot fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction.

    Methods: We performed a comprehensive characterisation of longitudinal antiviral B-cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP)and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells.

    Results: We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27-IgD- B cells and CD27/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection.

    Conclusion:  Our findings demonstrate that thrombocytopenia and kidneydysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus-infectedindividuals have significantly elevated levels of extracellular ATP incirculation.

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  • 22.
    Kerkman, Priscilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Tuiskunen-Bäck, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    The B cell response towards Puumala virus infection: can B cells be infected?2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 260-260Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Hantavirus infections are rodent-borne viruses causing potential lethal infections in humans. Different hantaviruses exist worldwide, reporting a fatality rate of up to 40%. The Puumala hantavirus (PUUV) is endemic in northern Sweden. This hantavirus strain has a relatively low fatality rate but the hospitalisation rate is high. No vaccine to the virus and no treatment for the disease exist. Despite differences in severity, the immune-mediated pathogenesis of Puumala virus infection is similar to that of highly lethal strains of hantavirus. It is currently unknown how the humoral immune system is affected during hantavirus infection.

    The aim of this study is to characterise how the humoral immune response is affected during Puumala virus infection. A large number of longitudinal patient samples have been collected. Here, we demonstrate the longitudinal kinetics of the B cell response during Puumala virus infection and show that there is a change in B cell populations during the course of the disease. Furthermore we show that B cells carry known hantavirus receptors. This suggests that Puumala virus may directly infect B cells. Infection of the B cells could affect their function and or phenotype explaining a different immune response. Importantly, in approximately 10–15% of Puumala infected patients we could detect antibodies that could neutralise other hantaviruses in vitro. Samples from these patients could help to generate a monoclonal antibody treatment potentially treating diseases caused by several hantavirus.

  • 23.
    Kolan, Shrikant S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Modulation of lymphoma growth by a selective serotonin receptor antagonist2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 343-343Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The mitogenic neurotransmitter, serotonin (5‐HT) acts as a growth factor for different types of non‐tumoral cells (e.g. vascular smooth muscle cells) and tumor cells (e.g. pancreatic carcinoid cells). The 5‐HT1A is a prototype receptor of 5‐HT1 family and as a G‐protein coupled receptor (GPCR), it exerts inhibitory action through Gi/o subunits and activating response via βγ subunits. 5‐HT1A receptors have long been implicated in the treatment of anxiety and depressive disorders. Apart from its role in neuropsychiatric diseases, 5‐HT1A receptor mediated signaling is important for T and B cell proliferation since blocking of the receptor has been linked to a reduced in vitro proliferative response after mitogenic stimulation. Here, we investigated the phenotypical and molecular effects of serotonin signaling by treating human B cell‐derived lymphoma cell lines with a selective 5‐HT1A antagonist. Our data show that repeated treatments with the 5‐HT1A antagonist resulted in significantly reduced proliferation in human B‐derived lymphoma cell lines. We demonstrate that the block in proliferation was associated with induction of apoptosis, DNA damage and morphological alterations of surviving cells. We also provide evidence that treatment of lymphoma B cells with the 5HT1A antagonist leads to activation of GSK3‐beta and a downregulation of c‐MYC and cyclin D1 mRNA transcripts. Collectively, our data indicate that modulation of serotonin signaling may have potential for treatment of B cell‐derived lymphomas.

  • 24.
    Kolan, Shrikant S
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling2019Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikel-id 4276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.

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  • 25.
    Lagerqvist, Nina
    et al.
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Maleki, Kimia T.
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Verner-Carlsson, Jenny
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Olausson, Mikaela
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Dillner, Joakim
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wigren Byström, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Monsen, Tor J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Eriksson, Jenny
    Region Västmanland, Västerås, Sweden.
    Bogdanovic, Gordana
    Karolinska University Hospital, Stockholm, Sweden.
    Muschiol, Sandra
    Karolinska University Hospital, Stockholm, Sweden.
    Ljunggren, Joel
    Region Västernorrland, County Hospital of Västernorrland, Sundsvall, Sweden.
    Repo, Johanna
    Region Västernorrland, County Hospital of Västernorrland, Sundsvall, Sweden.
    Kjerstadius, Torbjörn
    Region Värmland, Centralsjukhuset, Karlstad, Sweden.
    Muradrasoli, Shaman
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Brytting, Mia
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Szekely Björndal, Åsa
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Åkerlund, Thomas
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
    Nilsson, Charlotta
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Klingström, Jonas
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Evaluation of 11 SARS-CoV-2 antibody tests by using samples from patients with defined IgG antibody titers2021Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 7614Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We evaluated the performance of 11 SARS-CoV-2 antibody tests using a reference set of heat-inactivated samples from 278 unexposed persons and 258 COVID-19 patients, some of whom contributed serial samples. The reference set included samples with a variation in SARS-CoV-2 IgG antibody titers, as determined by an in-house immunofluorescence assay (IFA). The five evaluated rapid diagnostic tests had a specificity of 99.0% and a sensitivity that ranged from 56.3 to 81.6% and decreased with low IFA IgG titers. The specificity was > 99% for five out of six platform-based tests, and when assessed using samples collected ≥ 22 days after symptom onset, two assays had a sensitivity of > 96%. These two assays also detected samples with low IFA titers more frequently than the other assays. In conclusion, the evaluated antibody tests showed a heterogeneity in their performances and only a few tests performed well with samples having low IFA IgG titers, an important aspect for diagnostics and epidemiological investigations.

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  • 26.
    Lidström, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Cumming, Joshua
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Gaur, Rahul
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Frängsmyr, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Pateras, Ioannis S.
    2nd Department of Pathology, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Mickert, Matthias J.
    Lumito AB, Lund, Sweden.
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dongre, Mitesh
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer2023Ingår i: Cancer immunology research, ISSN 2326-6066, Vol. 11, nr 1, s. 72-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

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  • 27.
    Ljungquist, Oskar
    et al.
    Department of Translational Medicine, Clinical Infection Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Department of Infectious Diseases, Helsingborg Hospital, Helsingborg, Sweden.
    Lundgren, Maria
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Iliachenko, Elena
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Månsson, Fredrik
    Department of Translational Medicine, Clinical Infection Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden.
    Böttiger, Blenda
    Department of Clinical Microbiology, University and Regional Laboratories, Lund, Sweden.
    Landin-Olsson, Mona
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Science, Division of Internal Medicine, Lund University, Lund, Sweden.
    Wikén, Christian
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kjeldsen-Kragh, Jens
    Department of Clinical Immunology and Transfusion Medicine, Office of Medical Services, Lund, Sweden.
    Rasmussen, Magnus
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Kahn, Fredrik
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Holm, Karin
    Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
    Convalescent plasma treatment in severely immunosuppressed patients hospitalized with COVID-19: an observational study of 28 cases2022Ingår i: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 54, nr 4, s. 283-291Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Immunosuppressed patients are particularly vulnerable to severe infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), risking prolonged viremia and symptom duration. In this study we describe clinical and virological treatment outcomes in a heterogeneous group of patients with severe immunosuppression due to various causes suffering from COVID-19 infection, who were all treated with convalescent plasma (CCP) along with standard treatment.

    Methods: We performed an observational, retrospective case series between May 2020 to March 2021 at three sites in Skåne, Sweden, with a population of nearly 1.4 million people. All patients hospitalized for COVID-19 who received CCP with the indication severe immunosuppression as defined by the treating physician were included in the study (n = 28).

    Results: In total, 28 severely immunocompromised patients, half of which previously had been treated with rituximab, who had received in-hospital convalescent plasma treatment of COVID-19 were identified. One week after CCP treatment, 13 of 28 (46%) patients had improved clinically defined as a decrease of at least one point at the WHO-scale. Three patients had increased score points of whom two had died. For 12 patients, the WHO-scale was unchanged.

    Conclusion: As one of only few studies on CCP treatment of COVID-19 in hospitalized patients with severe immunosuppression, this study adds descriptive data. The study design prohibits conclusions on safety and efficacy, and the results should be interpreted with caution. Prospective, randomized trials are needed to investigate this further.

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  • 28.
    Maleki, Kimia T.
    et al.
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Tauriainen, Johanna
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    García, Marina
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Kerkman, Priscilla
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Christ, Wanda
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Dias, Joana
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Leeansyah, Edwin
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, China; Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ljunggren, Hans-Gustaf
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Björkström, Niklas K.
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sandberg, Johan K.
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Klingström, Jonas
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    MAIT cell activation is associated with disease severity markers in acute hantavirus infection2021Ingår i: Cell Reports Medicine, E-ISSN 2666-3791 , Vol. 2, nr 3, artikel-id 100220Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hantaviruses are zoonotic RNA viruses that cause severe acute disease in humans. Infected individuals have strong inflammatory responses that likely cause immunopathology. Here, we studied the response of mucosal-associated invariant T (MAIT) cells in peripheral blood of individuals with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala orthohantavirus, a hantavirus endemic in Europe. We show that MAIT cell levels decrease in the blood during HFRS and that residual MAIT cells are highly activated. This activation correlates with HFRS severity markers. In vitro activation of MAIT cells by hantavirus-exposed antigen-presenting cells is dependent on type I interferons (IFNs) and independent of interleukin-18 (IL-18). These findings highlight the role of type I IFNs in virus-driven MAIT cell activation and suggest a potential role of MAIT cells in the disease pathogenesis of viral infections.

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  • 29.
    Mittler, Eva
    et al.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    Serris, Alexandra
    CNRS UMR3569, Structural Virology Unit, Institut Pasteur, Paris, France.
    Esterman, Emma S.
    Adimab LLC, Lebanon, NH,USA.
    Florez, Catalina
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States; The Geneva Foundation, Tacoma, WA, USA.
    Polanco, Laura C.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    O'Brien, Cecilia M.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States; The Geneva Foundation, Tacoma, WA, USA.
    Slough, Megan M.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    Tynell, Janne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.
    Gröning, Remigius
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sun, Yan
    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
    Abelson, Dafna M.
    Mapp Biopharmaceutical Inc., San Diego, CA, USA.
    Wec, Anna Z.
    Adimab LLC, Lebanon, NH, USA.
    Haslwanter, Denise
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    Keller, Markus
    Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.
    Ye, Chunyan
    Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, United States.
    Bakken, Russel R.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
    Jangra, Rohit K.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    Dye, John M.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rappazzo, C. Garrett
    Adimab LLC, Lebanon, NH, USA.
    Ulrich, Rainer G.
    Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany; Partner site: Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Greifswald-Insel Riems, Germany.
    Zeitlin, Larry
    Mapp Biopharmaceutical Inc., San Diego, CA, USA.
    Geoghegan, James C.
    Adimab LLC, Lebanon, NH, USA.
    Bradfute, Steven B.
    Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, United States.
    Sidoli, Simone
    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Strandin, Tomas
    Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.
    Rey, Felix A.
    CNRS UMR3569, Structural Virology Unit, Institut Pasteur, Paris, France.
    Herbert, Andrew S.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, United States.
    Walker, Laura M.
    Adimab LLC, Lebanon, NH, USA.
    Chandran, Kartik
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
    Guardado-Calvo, Pablo
    CNRS UMR3569, Structural Virology Unit, Institut Pasteur, Paris, France.
    Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody2023Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 15, nr 700, artikel-id eadg1855Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.

  • 30.
    Mittler, Eva
    et al.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    Wec, Anna Z.
    Adimab, LLC, United States.
    Tynell, Janne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.
    Guardado-Calvo, Pablo
    Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Polanco, Laura C.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    O'Brien, Cecilia M.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, United States; The Geneva Foundation, Tacoma, WA 98402, USA.
    Slough, Megan M.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    Abelson, Dafna M.
    Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
    Serris, Alexandra
    Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France.
    Sakharkar, Mrunal
    Adimab, LLC, United States.
    Pehau-Arnaudet, Gerard
    Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France.
    Bakken, Russell R.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, United States.
    Geoghegan, James C.
    Adimab, LLC, United States.
    Jangra, Rohit K.
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    Keller, Markus
    Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany.
    Zeitlin, Larry
    Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
    Vapalahti, Olli
    Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland; Veterinary Biosciences, Veterinary Faculty, University of Helsinki, Helsinki, Finland.
    Ulrich, Rainer G.
    Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany; Deutsches Zentrum für Infektionsforschung, Partner site Hamburg-Lübeck- Borstel-Riems, Greifswald-Insel Riems, Germany.
    Bornholdt, Zachary A.
    Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rey, Felix A.
    Structural Virology Unit, Department of Virology, Institut Pasteur, Paris, France.
    Dye, John M.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, United States.
    Bradfute, Steven B.
    Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, United States.
    Strandin, Tomas
    Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, Helsinki, Finland.
    Herbert, Andrew S.
    U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, United States; The Geneva Foundation, Tacoma, WA 98402, USA.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Walker, Laura M.
    Adimab, LLC, United States.
    Chandran, Kartik
    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
    Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses2022Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 14, nr 636, artikel-id eabl5399Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the "capping loop" of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

  • 31.
    Normark, Johan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Vikström, Linnea
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Yong-Dae, Gwon
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Persson, Ida-Lisa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Edin, Alicia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Björsell, Tove
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Christ, Wanda
    Tevell, Staffan
    Evander, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
    Klingström, Jonas
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination2021Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 385, nr 11, s. 1049-1051Artikel i tidskrift (Refereegranskat)
  • 32. Oliveira, Mariana
    et al.
    Baptista, Marisa
    Keszei, Marton
    Snapper, Scott
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Thrasher, Adrian
    Andersson, John
    Westerberg, Lisa
    The Wiskott-Aldrich syndrome protein regulates antigen processing and presentation by dendritic cells2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 254-255Artikel i tidskrift (Övrigt vetenskapligt)
  • 33.
    Rosendal, Ebba
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Mihai, Ionut Sebastian
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). National Clinical Research School in Chronic Inflammatory Diseases (NCRSCID), Karolinska Institutet, Solna, Sweden.
    Becker, Miriam
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between The Medical School Hannover, The Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Das, Debojyoti
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Frängsmyr, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Persson, B. David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Swedish National Veterinary Institute (SVA), Uppsala, Sweden.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Gröning, Remigius
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Sartorius Corporate Research, Umeå, Sweden.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Henriksson, Johan
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lenman, Annasara
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections2022Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, nr 3, artikel-id e00892-22Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

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  • 34.
    Schagatay, Felix
    et al.
    Department of Infectious Diseases, CKF Region Västmanland, Västerås Hospital, Västerås, Sweden.
    Diamant, Klara
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Lidén, Mats
    Department of Radiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Edin, Alicia
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Anestesiologi och intensivvård.
    Athlin, Simon
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren, Olof
    Department of Laboratory medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Savilampi, Johanna
    Department of Anaesthesiology and Intensive Care, Örebro University, Örebro, Sweden.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lange, Anna
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Cajander, Sara
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-192022Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, artikel-id 945603Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored.

    Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19.

    Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI.

    Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97).

    Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

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  • 35.
    Schrottmaier, Waltraud C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Institute for Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.
    Salzmann, M.
    Badrnya, S.
    Morava, S.
    Luik, A-L
    Kral-Pointner, J. B.
    Mussbacher, M.
    Karlsson, M.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Assinger, A.
    Platelet-stored antibodies potently diminish viral infection in vitro and in vivo2019Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 227, nr S718, s. 187-187Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Besides their primary role in haemostasis, platelets are actively involved in immune responses as they respond to various inflammatory stimuli, including microbial infection. Further, platelets contain intracellular IgG, but their physiologic function remains unknown. Thus, we aimed to elucidate the function of platelet-derived IgGs and their effect on viral infections. Human and murine platelets contained IgG which were released upon shear stress. However, IgG loss did not correlate with P-Selectin exposure or CXCL4 release and α-granule deficient (Nbeal2-/-) platelets failed to show reduced IgG content and release, indicating an extragranular IgG storage site within platelets. While platelet IgG could derive from megakaryocytes that have taken up IgG from the bone marrow microenvironment, naïve platelets also took up IgG directly from plasma in vitro and in vivo. Murine platelets from anti-IAV IgG seropositive mice reduced IAV infection in vitro and in vivo more efficiently than plasma containing comparable IgG levels. Further, human platelets from anti-CMV IgG seropositive but not seronegative donors also potently neutralized in vitro CMV-infection of HUVEC under microvascular shear stress. Our data indicate that IgG storage in platelets may not be restricted to α-granules. Further, our results show that platelets have the potential to mediate potent IgG-mediated antiviral effects both in vitro and in vivo directly at foci of infection. This indicates that platelet-derived IgG may represent a yet unexplored mechanism for focused serological immunity.

  • 36. Sundling, Christopher
    et al.
    Ronnberg, Caroline
    Yman, Victor
    Asghar, Muhammad
    Jahnmatz, Peter
    Lakshmikanth, Tadepally
    Chen, Yang
    Mikes, Jaromir
    Forsell, Mattias N.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sonden, Klara
    Achour, Adnane
    Brodin, Petter
    Persson, Kristina E. M.
    Farnert, Anna
    B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets2019Ingår i: JCI Insight, ISSN 2379-3708, Vol. 4, nr 9, artikel-id e126492Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute Plasmodium fakiporum malaria for the first time or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that approximately 80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only approximately 40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared with individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay, with a half-life of approximately 300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary and secondary B cell responses during infection.

  • 37.
    Tuiskunen-Bäck, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rasmuson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Thunberg, Therese
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wigren Byström, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Andersson, Charlotta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Sjödin, Andreas
    CBRN Security and Defence, Swedish Defence Research Agency - FOI, Umeå, Sweden.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Clinical and genomic characterisation of a fatal Puumala orthohantavirus case with low levels of neutralising antibodies2022Ingår i: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 54, nr 10, s. 766-772Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Orthohantaviruses are rodent-borne emerging viruses that cause haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in America. Transmission between humans have been reported and the case-fatality rate ranges from 0.4% to 40% depending on virus strain. There is no specific and efficient treatment for patients with severe HFRS. Here, we characterised a fatal case of HFRS and sequenced the causing Puumala orthohantavirus (PUUV).

    METHODS: PUUV RNA and virus specific neutralising antibodies were quantified in plasma samples from the fatal case and other patients with non-fatal PUUV infection. To investigate if the causing PUUV strain was different from previously known strains, Sanger sequencing was performed directly from the patient's plasma. Biopsies obtained from autopsy were stained for immunohistochemistry.

    RESULTS: The patient had approximately tenfold lower levels of PUUV neutralising antibodies and twice higher viral load than was normally seen for patients with less severe PUUV infection. We could demonstrate unique mutations in the S and M segments of the virus that could have had an impact on the severity of infection. Due to the severe course of infection, the patient was treated with the bradykinin receptor inhibitor icatibant to reduce bradykinin-mediated vessel permeability and maintain vascular circulation.

    CONCLUSIONS: Our data suggest that bradykinin receptor inhibitor may not be highly efficient to treat patients that are at an advanced stage of HFRS. Low neutralising antibodies and high viral load at admission to the hospital were associated with the fatal outcome and may be useful for future predictions of disease outcome.

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  • 38.
    Vikström, Linnea
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Fjällström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Gwon, Yong-Dae
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sheward, Daniel J.
    The Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Wigren-Byström, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Evander, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Bladh, Oscar
    The Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Widerström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Molnar, Christian
    Familjeläkarna, Stockholm, Sweden.
    Rasmussen, Gunlög
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Bennet, Louise
    Department of Clinical Sciences, Clinical Studies Sweden, Forum South, Skåne University Hospital, Lund University, Lund, Sweden.
    Åberg, Mikael
    The Department of Medical Sciences, Clinical Chemistry and SciLifeLab, Uppsala University, Uppsala, Sweden.
    Björk, Jonas
    The Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
    Tevell, Staffan
    Faculty of Medicine and Health, The Department of Infectious Diseases, Karlstad Hospital and Centre for Clinical Research and Education, Region Värmland, Örebro University, Örebro, Sweden.
    Thålin, Charlotte
    The Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Blom, Kim
    The Swedish Public Health Agency, Stockholm, Sweden.
    Klingström, Jonas
    The Department of Biomedical Clinical Sciences, Linköpings University, Linköping, Sweden.
    Murrell, Ben
    The Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Johansson, Anders F.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Vaccine-induced correlate of protection against fatal COVID-19 in older and frail adults during waves of neutralization-resistant variants of concern: an observational study2023Ingår i: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 30, artikel-id 100646Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal COVID-19 among nursing homes residents.

    Methods: We performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort of nursing home residents in Sweden. We analyzed immunological and registry data from 16 September 2021 to 31 August 2022 with follow-up of deaths to 30 September 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves.

    Findings: A total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG in blood and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the associated 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The death risk plateaued at population average above the lower 35th percentile of S-binding IgG.

    Interpretation: In the absence of neutralizing antibodies that protect from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal COVID-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern.

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  • 39.
    Waltraud, Schrottmaier
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Anna-Liisa, Luik
    Manuel, Salzmann
    Sigrun, Badrnya
    Susanne, Morava
    Julia, Kral-Pointner
    Mikael, Karlsson
    Alice, Assinger
    Mattias, Forsell
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Activation of circulating platelets leads to innate-like delivery of potent antiviral antibodies2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 278-278Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: Platelet activation and subsequent thrombus formation is a well‐defined process to maintain vascular integrity upon tissue damage. However, platelets are also activated by an array of inflammatory stimuli, including microbial infection. Further, circulating platelets contain intracellular IgG that are released upon activation.

    Aim: We aimed to elucidate the physiologic function of platelet‐derived IgGs and their effect on viral infections.

    Methods: IgG levels, subclass and light chain distributions were quantified by ELISA. For neutralization assays, CMV‐infected HUVECs were perfused with platelets or plasma of anti‐CMV IgG seropositive or seronegative donors before quantification of infection by IF or qPCR. IgG content of neonatal Fc‐receptor (FcRn)‐deficient or wild‐type murine megakaryocytes (MK) was measured by flow cytometry.

    Results: Human platelets can store and release anti‐IAV and anti‐CMV IgG. Platelets from anti‐CMV IgG seropositive but not seronegative donors potently neutralized in vitro CMV‐infection under microvascular shear stress. In spite of containing approximately 100‐fold less IgG, platelets were equally efficient at neutralization as plasma from the same donor. Platelets were not enriched for a specific IgG subclass, nor for a specific kappa or lambda light chain. As MKs contain FcRn, sequestration of IgG might occur in the shared microenvironment of MKs and plasma cells. Indeed, MK FcRn was partially responsible for IgG uptake and may thus rescue IgG from degradation after endocytosis.

    Conclusion: Our data show that platelets have the potential to mediate potent IgG‐mediated antiviral effects directly at foci of infection, indicating that platelet activation may represent a novel mechanism for focused serological immunity.

  • 40.
    Waltraud, Schrottmaier C.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Salzmann, Manuel
    Badrnya, Sigrun
    Mussbacher, Marion
    Kral-Pointner, Julia B.
    Morava, Susanne
    Pirabe, Anita
    Brunnthaler, Laura
    Yaiw, Koon C.
    Heber, Ulrike M.
    Pereyra, David
    Andersen, Jan T.
    Bergthaler, Andreas
    Söderberg-Nauclér, Cecilia
    Karlsson, Mikael C., I
    Assinger, Alice
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Platelets mediate serological memory to neutralize viruses in vitro and in vivo2020Ingår i: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 4, nr 16, s. 3971-3976Artikel i tidskrift (Refereegranskat)
  • 41.
    Waltraud, Schrottmaier
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Schmuckenschlager, Anna
    Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Thunberg, Therese
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wigren, Julia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Fors Connolly, Anne-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Assinger, Alice
    Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Direct and indirect effects of Puumala hantavirus on platelet function2024Ingår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 233, s. 41-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target.

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  • 42. Wec, Anna Z.
    et al.
    Haslwanter, Denise
    Abdiche, Yasmina N.
    Shehata, Laila
    Pedreno-Lopez, Nuria
    Moyer, Crystal L.
    Bornholdt, Zachary A.
    Lilov, Asparouh
    Nett, Juergen H.
    Jangra, Rohit K.
    Brown, Michael
    Watkins, David I.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rey, Felix A.
    Barba-Spaeth, Giovanna
    Chandran, Kartik
    Walker, Laura M.
    Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine2020Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, nr 12, s. 6675-6685Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A comprehensive understanding of the development and evolution of human B cell responses duced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a gh-throughput single B cell cloning technology to longitudinally track the human B cell response to the llow fever virus 17D (YFV-17D) vaccine. The earlymemory B cell (MBC) response was mediated by both assical immunoglobulin M (IgM) (IgM(+)CD27(+)) and switched immunoglobulin (swIg(+)) MBC pulations; however, classical IgM MBCs waned rapidly, whereas swIg(+) and atypical IgM(+) and IgD(+) MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

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  • 43.
    Wigren, Julia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Xerum AB, Umeå, Sweden.
    Vikström, Linnea
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gröning, Remigius
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Gwon, Yong-Dae
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Sharma, Atin
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Espaillat, Akbar
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Hanke, Leo
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    McInerney, Gerald
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Puhar, Andrea
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Thunberg, Therese
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Monsen, Tor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Elgh, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Evander, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Johansson, Anders F.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study2023Ingår i: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, nr 13, artikel-id 2200432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access. Rural regions are therefore often not represented in population-based data.

    Aim: The aim of this retrospective cohort study was to develop and implement a strategy for at-home testing in a rural region of Sweden during spring 2021, and to evaluate its role to provide equal health care for its inhabitants.

    Methods: We developed a sensitive method to measure antibodies to the S-protein of SARS-CoV-2 and optimised this assay for clinical use together with a strategy of at-home capillary blood sampling.

    Results: We demonstrated that our ELISA gave comparable results after analysis of capillary blood or serum from SARS-CoV-2-experienced individuals. We demonstrated stability of the assay under conditions that reflected temperature and humidity during winter or summer. By assessment of capillary blood samples from 4,122 individuals, we could show both feasibility of the strategy and that implementation shifted the geographical spread of testing in favour of rural areas.

    Conclusion: Implementation of at-home sampling enabled citizens living in remote rural areas access to centralised and sensitive laboratory antibody tests. The strategy for testing used here could therefore enable disease control authorities to get rapid access to information concerning immunity to infectious diseases, even across vast geographical distance.

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