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Publications (10 of 66) Show all publications
Dhillon, A., Persson, B. D., Volkov, A. N., Sülzen, H., Kádek, A., Pompach, P., . . . Zoll, S. (2024). Structural insights into the interaction between adenovirus C5 hexon and human lactoferrin. Journal of Virology, 98(3), Article ID e01576-23.
Open this publication in new window or tab >>Structural insights into the interaction between adenovirus C5 hexon and human lactoferrin
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2024 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 98, no 3, article id e01576-23Article in journal (Refereed) Published
Abstract [en]

Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human AdV species C types, such as HAdV-C5, utilize the Coxsackieadenovirus receptor (CAR) for attachment and subsequently integrins for entry. CAR and integrins are however located deep within the tight junctions in the mucosa where they would not be easily accessible. Recently, a model for CAR-independent AdV entry was proposed. In this model, human lactoferrin (hLF), an innate immune protein, aids the viral uptake into epithelial cells by mediating interactions between the major capsid protein, hexon, and yet unknown host cellular receptor(s). However, a detailed understanding of the molecular interactions driving this mechanism is lacking. Here, we present a new cryo-EM structure of HAdV-5C hexon at high resolution alongside a hybrid structure of HAdV-5C hexon complexed with human lactoferrin (hLF). These structures reveal the molecular determinants of the interaction between hLF and HAdV-C5 hexon. hLF engages hexon primarily via its N-terminal lactoferricin (Lfcin) region, interacting with hexon’s hypervariable region 1 (HVR-1). Mutational analyses pinpoint critical Lfcin contacts and also identify additional regions within hLF that critically contribute to hexon binding. Our study sheds more light on the intricate mechanism by which HAdV-C5 utilizes soluble hLF/Lfcin for cellular entry. These findings hold promise for advancing gene therapy applications and inform vaccine development.

Keywords
adenovirus, cryo-EM, immune evasion, lactoferrin, viral entry
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-222882 (URN)10.1128/jvi.01576-23 (DOI)001158715300002 ()38323814 (PubMedID)2-s2.0-85188480462 (Scopus ID)
Funder
EU, Horizon 2020European Regional Development Fund (ERDF)EU, Horizon 2020, ERC StG-2017 759661
Available from: 2024-04-12 Created: 2024-04-12 Last updated: 2024-04-12Bibliographically approved
Becker, M., Conca, D. V., Dorma, N., Mistry, N., Hahlin, E., Frängsmyr, L., . . . Gerold, G. (2023). Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells. Journal of Virology, 97(10)
Open this publication in new window or tab >>Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells
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2023 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 97, no 10Article in journal (Refereed) Published
Abstract [en]

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. EAdVs have a unique capsid architecture and exhibit — unlike other human adenoviruses — a relatively strict tropism for gastrointestinal tissues with, to date, understudied infection mechanism and unknown target cells. In this study, we turn to potentially limiting host factors by comparing EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking, and transmission electron microscopy. Our analyses highlight kinetic advantages for EAdVs in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake, and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understanding pathogenesis and developing new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a cell line originating from a relevant tissue. IMPORTANCE Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.

Keywords
clathrin-mediated endocytosis, electron microscopy, enteric adenovirus, single particle tracking, virus entry
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-216662 (URN)10.1128/jvi.00770-23 (DOI)37823645 (PubMedID)2-s2.0-85175844402 (Scopus ID)
Funder
Swedish Research Council, 2020-06242Swedish Research Council, 2019-01472Knut and Alice Wallenberg FoundationKnut and Alice Wallenberg Foundation
Available from: 2023-11-27 Created: 2023-11-27 Last updated: 2023-11-28Bibliographically 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
Johansson, E., Caraballo, R., Zocher, G., Mistry, N., Arnberg, N., Stehle, T. & Elofsson, M. (2022). Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction. RSC Advances, 12(4), 2319-2331
Open this publication in new window or tab >>Exploring divalent conjugates of 5-N-acetyl-neuraminic acid as inhibitors of coxsackievirus A24 variant (CVA24v) transduction
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2022 (English)In: RSC Advances, E-ISSN 2046-2069, Vol. 12, no 4, p. 2319-2331Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) is responsible for several outbreaks and two pandemics of the highly contagious eye infection acute hemorrhagic conjunctivitis (AHC). Currently, neither prevention (vaccines) nor treatments (antivirals) are available for combating this disease. CVA24v attaches to cells by binding Neu5Ac-containing glycans on the surface of cells which facilitates entry. Previously, we have demonstrated that pentavalent Neu5Ac conjugates attenuate CVA24v infection of human corneal epithelial (HCE) cells. In this study, we report on the structure-based design of three classes of divalent Neu5Ac conjugates, with varying spacer lengths, and their effect on CVA24v transduction in HCE cells. In relative terms, the most efficient class of divalent Neu5Ac conjugates are more efficient than the pentavalent Neu5Ac conjugates previously reported.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2022
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-192370 (URN)10.1039/d1ra08968d (DOI)000742407000001 ()2-s2.0-85123934421 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2022-02-11 Created: 2022-02-11 Last updated: 2022-09-15Bibliographically approved
Benkő, M., Aoki, K., Arnberg, N., Davison, A. J., Echavarría, M., Hess, M., . . . Harrach, B. (2022). ICTV Virus Taxonomy Profile: Adenoviridae 2022. Journal of General Virology, 103(3)
Open this publication in new window or tab >>ICTV Virus Taxonomy Profile: Adenoviridae 2022
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2022 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 103, no 3Article in journal (Refereed) Published
Abstract [en]

The family Adenoviridae includes non-enveloped viruses with linear dsDNA genomes of 25-48 kb and medium-sized icosahedral capsids. Adenoviruses have been discovered in vertebrates from fish to humans. The family is divided into six genera, each of which is more common in certain animal groups. The outcome of infection may vary from subclinical to lethal disease. This is a summary of the ICTV Report on the family Adenoviridae, which is available at ictv.global/report/adenoviridae.

Place, publisher, year, edition, pages
Microbiology Society, 2022
Keywords
Adenoviridae, Atadenovirus, Aviadenovirus, Ichtadenovirus, ICTV Report, Mastadenovirus, Siadenovirus, Taxonomy, Testadenovirus
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-193228 (URN)10.1099/jgv.0.001721 (DOI)000783796800003 ()35262477 (PubMedID)2-s2.0-85126076828 (Scopus ID)
Available from: 2022-03-21 Created: 2022-03-21 Last updated: 2023-09-05Bibliographically approved
Persson, B. D., Nord, S., Lindquist, R., Danskog, K., Överby, A. K., Kohl, A., . . . Arnberg, N. (2021). BAF45b is required for efficient zika virus infection of HAP1 cells. Viruses, 13(10), Article ID 2007.
Open this publication in new window or tab >>BAF45b is required for efficient zika virus infection of HAP1 cells
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2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 10, article id 2007Article in journal (Refereed) Published
Abstract [en]

The 2016 Zika virus (ZIKV) epidemic illustrates the impact of flaviviruses as emerging human pathogens. For unknown reasons, ZIKV replicates more efficiently in neural progenitor cells (NPCs) than in postmitotic neurons. Here, we identified host factors used by ZIKV using the NCI-60 library of cell lines and COMPARE analysis, and cross-analyzed this library with two other libraries of host factors with importance for ZIKV infection. We identified BAF45b, a subunit of the BAF (Brg1/Brm-associated factors) protein complexes that regulate differentiation of NPCs to post-mitotic neurons. ZIKV (and other flaviviruses) infected HAP1 cells deficient in expression of BAF45b and other BAF subunits less efficiently than wildtype (WT) HAP1 cells. We concluded that subunits of the BAF complex are important for infection of ZIKV and other flavivirus. Given their function in cell and tissue differentiation, such regulators may be important determinants of tropism and pathogenesis of arthropod-borne flaviviruses.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
BAF45b, DPF1, Flavivirus, Zika virus
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-188850 (URN)10.3390/v13102007 (DOI)000792951900009 ()2-s2.0-85117010328 (Scopus ID)
Funder
EU, Horizon 2020, 734584Swedish Research Council, 2017-02438Swedish Research Council, 2016-00968
Available from: 2021-10-25 Created: 2021-10-25 Last updated: 2024-01-17Bibliographically approved
Johansson, E., Caraballo, R., Hurdiss, D. L., Mistry, N., Andersson, C. D., Thompson, R. F., . . . Elofsson, M. (2021). Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates. International Journal of Molecular Sciences, 22(16), Article ID 8418.
Open this publication in new window or tab >>Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 16, article id 8418Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
5-N-acetylneuraminic acid, Antivirals, Conjunctivitis, Coxsackievirus A24v, Cryo-EM, Multivalency, Sialic acid conjugates
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-186555 (URN)10.3390/ijms22168418 (DOI)000689130700001 ()2-s2.0-85111762142 (Scopus ID)
Available from: 2021-08-11 Created: 2021-08-11 Last updated: 2023-09-05Bibliographically approved
Ballmann, M. Z., Raus, S., Engelhart, R., Kaján, G. L., Beqqali, A., Hadoke, P. W. .., . . . Baker, A. H. (2021). Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development. Journal of Virology, 95(22), Article ID e00387-21.
Open this publication in new window or tab >>Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development
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2021 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 95, no 22, article id e00387-21Article in journal (Refereed) Published
Abstract [en]

Preexisting immune responses toward adenoviral vectors limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest in vectorizing novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full-genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton base, which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor-binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver, and spleen and triggered robust inflammatory immune responses. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination.

Place, publisher, year, edition, pages
American Society for Microbiology, 2021
Keywords
Cell and tissue transduction, Expression vector, Low seroprevalence, Novel adenovirus serotype, Potent T-cell responses
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-189474 (URN)10.1128/JVI.00387-21 (DOI)000718339200005 ()34469243 (PubMedID)2-s2.0-85118238152 (Scopus ID)
Funder
EU, Horizon 2020, 825670EU, FP7, Seventh Framework Programme, 324325
Available from: 2021-11-16 Created: 2021-11-16 Last updated: 2023-09-05Bibliographically approved
Persson, B. D., Lijo, J., Rafie, K., Strebl, M., Frängsmyr, L., Ballmann, M. Z., . . . Arnberg, N. (2021). Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46. Proceedings of the National Academy of Sciences of the United States of America, 118(3), Article ID e2020732118.
Open this publication in new window or tab >>Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 3, article id e2020732118Article in journal (Refereed) Published
Abstract [en]

Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.

Place, publisher, year, edition, pages
National Academy of Sciences, 2021
Keywords
adenovirus, hexon, CD46, receptor, vaccine
National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-180646 (URN)10.1073/pnas.2020732118 (DOI)000609633900068 ()33384338 (PubMedID)2-s2.0-85099119953 (Scopus ID)
Available from: 2021-02-24 Created: 2021-02-24 Last updated: 2021-02-24Bibliographically approved
Jakobsson, J., Cotgreave, I., Furberg, M., Arnberg, N. & Svensson, M. B. (2021). Potential physiological and cellular mechanisms of exercise that decrease the risk of severe complications and mortality following sars-cov-2 infection. Sports, 9(9), Article ID 121.
Open this publication in new window or tab >>Potential physiological and cellular mechanisms of exercise that decrease the risk of severe complications and mortality following sars-cov-2 infection
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2021 (English)In: Sports, E-ISSN 2075-4663, Vol. 9, no 9, article id 121Article, review/survey (Refereed) Published
Abstract [en]

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has unmasked mankind's vulnerability to biological threats. Although higher age is a major risk factor for disease severity in COVID-19, several predisposing risk factors for mortality are related to low cardiorespiratory and metabolic fitness, including obesity, cardiovascular disease, diabetes, and hypertension. Reaching physical activity (PA) guideline goals contribute to protect against numerous immune and inflammatory disorders, in addition to multi-morbidities and mortality. Elevated levels of cardiorespiratory fitness, being non-obese, and regular PA improves immunological function, mitigating sustained low-grade systemic inflammation and age-related deterioration of the immune system, or immunosenescence. Regular PA and being non-obese also improve the antibody response to vaccination. In this review, we highlight potential physiological, cellular, and molecular mechanisms that are affected by regular PA, increase the host antiviral defense, and may determine the course and outcome of COVID-19. Not only are the immune system and regular PA in relation to COVID-19 discussed, but also the cardiovascular, respiratory, renal, and hormonal systems, as well as skeletal muscle, epigenetics, and mitochondrial function.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
COVID-19, Exercise, Health, Immunology, Obesity, Physical activity, SARS-CoV-2, Virus
National Category
Immunology in the medical area Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-187696 (URN)10.3390/sports9090121 (DOI)000702059300001 ()2-s2.0-85114293725 (Scopus ID)
Available from: 2021-09-23 Created: 2021-09-23 Last updated: 2023-09-05Bibliographically approved
Projects
Virus receptors: implications for tropism, treatment and targeting [2010-03078_VR]; Umeå UniversityVirus receptors: implications for tropism, treatment and targeting [2013-02753_VR]; Umeå UniversityHost-glycome regulation of virus adhesion, tropism, and infection. [2013-08616_VR]; Umeå UniversityVirus-glycan interactions: implications for tropism, treatment and targeting [2017-00859_VR]; Umeå UniversityViral gastroenteritis: models, molecules, and mechanisms [2019-01472_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7069-6678

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