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Forsell, Mattias N. E.ORCID iD iconorcid.org/0000-0001-6904-742x
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Publications (10 of 44) Show all publications
Waltraud, S., Schmuckenschlager, A., Thunberg, T., Wigren, J., Fors Connolly, A.-M., Assinger, A., . . . Forsell, M. N. E. (2024). Direct and indirect effects of Puumala hantavirus on platelet function. Thrombosis Research, 233, 41-54
Open this publication in new window or tab >>Direct and indirect effects of Puumala hantavirus on platelet function
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2024 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 233, p. 41-54Article in journal (Refereed) Published
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.

Keywords
Hemorrhagic fever with renal syndrome, Immunothrombosis, Infection, Platelet dysfunction, Puumala hantavirus, Thrombocytopenia
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-217532 (URN)10.1016/j.thromres.2023.11.017 (DOI)2-s2.0-85177814613 (Scopus ID)
Funder
Region Västerbotten, RV-967545Region Västerbotten, RV-734361Umeå UniversitySwedish Heart Lung Foundation, 20170334Swedish Research Council, 2020-06235The Kempe Foundations, SMK-1560
Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2023-12-14Bibliographically approved
Rosenbaum, W., Bovinder Ylitalo, E., Castel, G., Sjödin, A., Larsson, P., Wigren Byström, J., . . . Tuiskunen-Bäck, A. (2024). Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles. Journal of Clinical Virology, 172, Article ID 105672.
Open this publication in new window or tab >>Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles
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2024 (English)In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 172, article id 105672Article in journal (Refereed) Published
Abstract [en]

Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality rate, 0.5–40 %, depending on the virus species, and no vaccine or effective treatment for severe Orthohantavirus infections exists. In Europe, the Puumala virus (PUUV), carried by the bank vole Myodes glareolus, causes a milder form of HFRS. Despite the reliance on serology and PCR for diagnosis, the three genomic segments of Swedish wild-type PUUV have yet to be completely sequenced.

We have developed a targeted hybrid-capture method aimed at comprehensive genomic sequencing of wild-type PUUV isolates and the identification of other Orthohantaviruses. Our custom-designed panel includes >11,200 probes covering the entire Orthohantavirus genus. Using this panel, we sequenced complete viral genomes from bank vole lung tissue, human plasma samples, and cell-cultured reference strains. Analysis revealed that Swedish PUUV isolates belong to the Northern Scandinavian lineage, with nucleotide diversity ranging from 2.8 % to 3.7 % among them. Notably, no significant genotypic differences were observed between the viral sequences from reservoirs and human cases except in the nonstructural protein.

Despite the high endemicity of PUUV in Northern Sweden, these are the first complete Swedish wild-type PUUV genomes and substantially increase our understanding of PUUV evolution and epidemiology. The panel's sensitivity enables genomic sequencing of human samples with viral RNA levels reflecting the natural progression of infection and underscores our panel's diagnostic value, and could help to uncover novel Orthohantavirus transmission routes.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Targeted sequencing, Whole-genome sequencing, Puumala virus, Orthohantaviruses, Hemorrhagic fever with renal syndrome, Diagnostics
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-223355 (URN)10.1016/j.jcv.2024.105672 (DOI)38574565 (PubMedID)2-s2.0-85189510700 (Scopus ID)
Funder
Swedish Research Council, 2020-06235Lars Hierta Memorial Foundation, FO2021-0251O.E. och Edla Johanssons vetenskapliga stiftelseRegion Västerbotten, RV-970009Region Västerbotten, RV-982503Stiftelsen Seth M. Kempes Minnes Stipendiefond, SMK21-0039
Available from: 2024-04-15 Created: 2024-04-15 Last updated: 2024-04-16Bibliographically approved
Wigren, J., Vikström, L., Rosendal, E., Gröning, R., Gwon, Y.-D., Nilsson, E., . . . Forsell, M. N. E. (2023). 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 study. Eurosurveillance, 28(13), Article ID 2200432.
Open this publication in new window or tab >>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 study
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2023 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 13, article id 2200432Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
European Centre for Disease Control and Prevention (ECDC), 2023
Keywords
coronavirus disease (COVID-19), laboratory, surveillance, Sweden
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-206673 (URN)10.2807/1560-7917.ES.2023.28.13.2200432 (DOI)000971868200003 ()36995373 (PubMedID)2-s2.0-85151573640 (Scopus ID)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-09-05Bibliographically approved
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
Ahmad, I., Edin, A., Granvik, C., Kumm Persson, L., Tevell, S., Månsson, E., . . . Normark, J. (2023). High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19. Frontiers In Public Health, 11, Article ID 1104267.
Open this publication in new window or tab >>High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19
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2023 (English)In: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, article id 1104267Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
COVID-19, EQ-5D, long-COVID, PACS, Post COVID-19 condition (PCC), post-acute COVID syndrome (PACS), SARS-CoV-2
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-205360 (URN)10.3389/fpubh.2023.1104267 (DOI)000937266000001 ()36817925 (PubMedID)2-s2.0-85148359690 (Scopus ID)
Funder
Nyckelfonden, OLL-938628Nyckelfonden, OLL-961416Region Västmanland, 20201009Swedish Research Council, 2020-06235Swedish Heart Lung Foundation, 20200325Swedish Heart Lung Foundation, 20210078Knut and Alice Wallenberg Foundation, VC-2020-0015Umeå UniversityRegion Västerbotten, RV-938855Region Värmland, LIVFOU-939646
Available from: 2023-03-29 Created: 2023-03-29 Last updated: 2023-10-30
Gröning, R., Dernstedt, A., Ahlm, C., Normark, J., Sundström, P. & Forsell, M. N. E. (2023). Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption. Frontiers in Immunology, 14, Article ID 1219560.
Open this publication in new window or tab >>Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1219560Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
B cell immunology, COVID-19, multiple sclerosis, rituximab, vaccination
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-212992 (URN)10.3389/fimmu.2023.1219560 (DOI)37575257 (PubMedID)2-s2.0-85167514064 (Scopus ID)
Funder
Region Västerbotten, RV-969133Swedish Research Council, 2020-0625Swedish Research Council, 2021-04665Knut and Alice Wallenberg Foundation, VA-2021-0018Knut and Alice Wallenberg Foundation, VA-2022-0008Science for Life Laboratory, SciLifeLab
Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2024-01-17Bibliographically approved
Cable, J., Graham, B. S., Koup, R. A., Seder, R. A., Karikó, K., Pardi, N., . . . Bekker, L.-G. (2023). Progress in vaccine development for infectious diseases: a Keystone Symposia report. Annals of the New York Academy of Sciences, 1524(1), 65-86
Open this publication in new window or tab >>Progress in vaccine development for infectious diseases: a Keystone Symposia report
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2023 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1524, no 1, p. 65-86Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
antigen design, mRNA vaccines, structural vaccinology, vaccine delivery, vaccine hesitancy, vaccines
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-212064 (URN)10.1111/nyas.14975 (DOI)000963643400001 ()37020354 (PubMedID)2-s2.0-85163921821 (Scopus ID)
Funder
NIH (National Institutes of Health)
Available from: 2023-07-18 Created: 2023-07-18 Last updated: 2023-07-18Bibliographically approved
Björsell, T., Sundh, J., Lange, A., Ahlm, C., Forsell, M. N. E., Tevell, S., . . . Cajander, S. (2023). Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients. Journal of Internal Medicine, 293(5), 600-614
Open this publication in new window or tab >>Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients
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2023 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 293, no 5, p. 600-614Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
breathlessness, COVID-19, diffusion capacity, post-acute COVID-19 syndrome, spirometry
National Category
Respiratory Medicine and Allergy General Practice
Identifiers
urn:nbn:se:umu:diva-205377 (URN)10.1111/joim.13614 (DOI)000936826900001 ()36815689 (PubMedID)2-s2.0-85148632325 (Scopus ID)
Funder
Nyckelfonden, OLL-938628Nyckelfonden, OLL-961416Swedish Research Council, 2020-06235Swedish Research Council, 2016-06514Swedish Heart Lung Foundation, 20200325Swedish Heart Lung Foundation, 20210078Knut and Alice Wallenberg Foundation, VC-2020-0015Umeå University, RV‐938855Region Västerbotten, RV-938855Region Värmland, LIVFOU-939646
Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2023-07-14Bibliographically approved
Blom, K., Fjällström, P., Molnár, C., Åberg, M., Vikström, L., Wigren, J., . . . Johansson, A. (2023). SARS-CoV-2-related mortality decrease in nursing home residents given multiple COVID-19 boosters [Letter to the editor]. The Lancet - Infectious diseases, 23(10), e393-e394
Open this publication in new window or tab >>SARS-CoV-2-related mortality decrease in nursing home residents given multiple COVID-19 boosters
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2023 (English)In: The Lancet - Infectious diseases, ISSN 1473-3099, E-ISSN 1474-4457, Vol. 23, no 10, p. e393-e394Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-215072 (URN)10.1016/S1473-3099(23)00548-0 (DOI)37716359 (PubMedID)2-s2.0-85172367341 (Scopus ID)
Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2024-01-17Bibliographically approved
Mittler, E., Serris, A., Esterman, E. S., Florez, C., Polanco, L. C., O'Brien, C. M., . . . Guardado-Calvo, P. (2023). Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody. Science Translational Medicine, 15(700), Article ID eadg1855.
Open this publication in new window or tab >>Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
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2023 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 15, no 700, article id eadg1855Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2023
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-211153 (URN)10.1126/scitranslmed.adg1855 (DOI)37315110 (PubMedID)2-s2.0-85161965332 (Scopus ID)
Available from: 2023-07-03 Created: 2023-07-03 Last updated: 2023-07-03Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6904-742x

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