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Rodrigues, R., Danskog, K., Överby, A. K. & Arnberg, N. (2019). Characterizing the cellular attachment receptor for Langat virus. PLoS ONE, 14(6), Article ID e0217359.
Open this publication in new window or tab >>Characterizing the cellular attachment receptor for Langat virus
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217359Article in journal (Refereed) Published
Abstract [en]

Tick-borne encephalitis infections have increased the last 30 years. The mortality associated to this viral infection is 0.5 to 30% with a risk of permanent neurological sequelae, however, no therapeutic is currently available. The first steps of virus-cell interaction, such as attachment and entry, are of importance to understand pathogenesis and tropism. Several molecules have been shown to interact with tick-borne encephalitis virus (TBEV) at the plasma membrane surface, yet, no studies have proven that these are specific entry receptors. In this study, we set out to characterize the cellular attachment receptor(s) for TBEV using the naturally attenuated member of the TBEV complex, Langat virus (LGTV), as a model. Inhibiting or cleaving different molecules from the surface of A549 cells, combined with inhibition assays using peptide extracts from high LGTV binding cells, revealed that LGTV attachment to host cells is dependent on plasma membrane proteins, but not on glycans or glycolipids, and suggested that LGTV might use different cellular attachment factors on different cell types. Based on this, we developed a transcriptomic approach to generate a list of candidate attachment and entry receptors. Our findings shed light on the first step of the flavivirus life-cycle and provide candidate receptors that might serve as a starting point for future functional studies to identify the specific attachment and/or entry receptor for LGTV and TBEV.

Place, publisher, year, edition, pages
Public Library Science, 2019
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-161188 (URN)10.1371/journal.pone.0217359 (DOI)000470086200012 ()31163044 (PubMedID)
Funder
Swedish Research Council, 349-2007-8673
Available from: 2019-06-28 Created: 2019-06-28 Last updated: 2019-07-10Bibliographically approved
Chandra, N., Frängsmyr, L. & Arnberg, N. (2019). Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus. Viruses, 11(3), Article ID E242.
Open this publication in new window or tab >>Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus
2019 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, no 3, article id E242Article in journal (Refereed) Published
Abstract [en]

Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
GAG-mimetic, adenovirus, cellular receptor, decoy receptor, epidemic keratoconjunctivitis, glycosaminoglycans
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-158516 (URN)10.3390/v11030242 (DOI)000464389700002 ()30870979 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2013.0019
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-08-28Bibliographically approved
Chandra, N., Frängsmyr, L., Imhof, S., Caraballo, R., Elofsson, M. & Arnberg, N. (2019). Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment. Viruses, 11(5), Article ID 395.
Open this publication in new window or tab >>Sialic Acid-Containing Glycans as Cellular Receptors for Ocular Human Adenoviruses: Implications for Tropism and Treatment
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2019 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, no 5, article id 395Article in journal (Refereed) Published
Abstract [en]

Human adenoviruses (HAdV) are the most common cause of ocular infections. Species B human adenovirus type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause epidemic keratoconjunctivitis (EKC). Recently, HAdV-D53, -D54, and -D56 emerged as new EKC-causing agents. HAdV-E4 is associated with both PCF and EKC. We have previously demonstrated that HAdV-D37 uses sialic acid (SA)-containing glycans as cellular receptors on human corneal epithelial (HCE) cells, and the virus interaction with SA is mediated by the knob domain of the viral fiber protein. Here, by means of cell-based assays and using neuraminidase (a SA-cleaving enzyme), we investigated whether ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells. We found that HAdV-E4 and -D56 infect HCE cells independent of SAs, whereas HAdV-D53 and -D64 use SAs as cellular receptors. HAdV-D8 and -D54 fiber knobs also bound to cell-surface SAs. Surprisingly, HCE cells were found resistant to HAdV-B3 infection. We also demonstrated that the SA-based molecule i.e., ME0462, designed to bind to SA-binding sites on the HAdV-D37 fiber knob, efficiently prevents binding and infection of several EKC-causing HAdVs. Surface plasmon resonance analysis confirmed a direct interaction between ME0462 and fiber knobs. Altogether, we demonstrate that SA-containing glycans serve as receptors for multiple EKC-causing HAdVs, and, that SA-based compound function as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
adenovirus, cellular receptor, epidemic keratoconjunctivitis, pharyngoconjunctival fever, sialic acid, tropism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-159268 (URN)10.3390/v11050395 (DOI)000472676600006 ()31035532 (PubMedID)2-s2.0-85065483937 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2019-05-23 Created: 2019-05-23 Last updated: 2019-08-28Bibliographically approved
Chandra, N., Liu, Y., Liu, J.-X., Frängsmyr, L., Wu, N., Silva, L. M., . . . Arnberg, N. (2019). Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37. Viruses, 11(3), Article ID E247.
Open this publication in new window or tab >>Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37
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2019 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, no 3, article id E247Article in journal (Refereed) Published
Abstract [en]

Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
adenovirus, antiviral drugs, cellular receptor, decoy receptor, epidemic keratoconjunctivitis, glycosaminoglycan, tropism
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-158515 (URN)10.3390/v11030247 (DOI)000464389700003 ()30871026 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2013.0019Swedish Research Council, 2018-02401Västerbotten County CouncilWellcome trust, 099197MA
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-08-28Bibliographically approved
Kaján, G. L., Lipiec, A., Bartha, D., Allard, A. & Arnberg, N. (2018). A multigene typing system for human adenoviruses reveals a new genotype in a collection of Swedish clinical isolates. PLoS ONE, 13(12), Article ID e0209038.
Open this publication in new window or tab >>A multigene typing system for human adenoviruses reveals a new genotype in a collection of Swedish clinical isolates
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209038Article in journal (Refereed) Published
Abstract [en]

Human adenoviruses (HAdVs) are common pathogens that can cause respiratory, gastrointestinal, urogenital, and ocular infections. They are divided into seven species containing 85 genotypes. Straightforward typing systems might help epidemiological investigations. As homologous recombination frequently shapes the evolution of HAdVs, information on a single gene is seldom sufficient to allow accurate and precise typing, and complete genome-based methods are recommended. Even so, complete genome analyses are not always easy to perform for practical reasons, and in such cases a multigene system can provide considerably more information about the strain under investigation than single-gene-based methods. Here we present a rapid, generic, multigene typing system for HAdVs based on three main deterministic regions of these viruses. Three PCR systems were used to amplify the genes encoding the DNA polymerase, the penton base hypervariable Arg-Gly-Asp-containing loop, and the hexon loop 1 (hypervariable region 1–6). Using this system, we typed 281 clinical isolates, detected members of six out of seven HAdV species (Human mastadenovirus AF), and could also detect not only divergent strains of established types but also a new recombinant strain with a previously unpublished combination of adenovirus genomes. This strain was accepted by the Human Adenovirus Working Group as a novel genotype: HAdV-86. Seven strains that could not be typed with sufficient accuracy were also investigated using a PCR based on part of the fiber gene. By analysis of corresponding sequences of the 86 known HAdV genotypes, we determined that the proposed typing system should be able to distinguish all non-recombinant types, and with additional fiber information, all known HAdV genotypes.

Place, publisher, year, edition, pages
Public Library Science, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-155105 (URN)10.1371/journal.pone.0209038 (DOI)000453248000040 ()30550551 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Rajan, A., Persson, B. D., Frängsmyr, L., Olofsson, A., Sandblad, L., Heino, J., . . . Arnberg, N. (2018). Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of Ht-29 cells. Scientific Reports, 8(1), Article ID 10019.
Open this publication in new window or tab >>Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of Ht-29 cells
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 10019Article in journal (Refereed) Published
Abstract [en]

The enteric species F human adenovirus types 40 and 41 (HAdV-40 and -41) are the third most common cause of infantile gastroenteritis in the world. Knowledge about HAdV-40 and -41 cellular infection is assumed to be fundamentally different from that of other HAdVs since HAdV-40 and -41 penton bases lack the αV-integrin-interacting RGD motif. This motif is used by other HAdVs mainly for internalization and endosomal escape. We hypothesised that the penton bases of HAdV-40 and -41 interact with integrins independently of the RGD motif. HAdV-41 transduction of a library of rodent cells expressing specific human integrin subunits pointed to the use of laminin-binding α2-, α3- and α6-containing integrins as well as other integrins as candidate co-receptors. Specific laminins prevented internalisation and infection, and recombinant, soluble HAdV-41 penton base proteins prevented infection of human intestinal HT-29 cells. Surface plasmon resonance analysis demonstrated that HAdV-40 and -41 penton base proteins bind to α6-containing integrins with an affinity similar to that of previously characterised penton base:integrin interactions. With these results, we propose that laminin-binding integrins are co-receptors for HAdV-40 and -41.

Place, publisher, year, edition, pages
Springer Nature, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146978 (URN)10.1038/s41598-018-28255-7 (DOI)000437097000036 ()29968781 (PubMedID)2-s2.0-85049507353 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-08-29Bibliographically approved
Duffy, M. R., Alonso-Padilla, J., John, L., Chandra, N., Khan, S., Ballmann, M. Z., . . . Lemckert, A. (2018). Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56. Journal of General Virology, 99, 135-147
Open this publication in new window or tab >>Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56
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2018 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 99, p. 135-147Article in journal (Refereed) Published
Abstract [en]

The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.

Keywords
adenovirus, HAdV-56, gene therapy, vaccine vector
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-143059 (URN)10.1099/jgv.0.000978 (DOI)000431016500015 ()29154744 (PubMedID)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
Lasswitz, L., Chandra, N., Arnberg, N. & Gerold, G. (2018). Glycomics and Proteomics Approaches to Investigate Early Adenovirus-Host Cell Interactions. Journal of Molecular Biology, 430(13), 1863-1882
Open this publication in new window or tab >>Glycomics and Proteomics Approaches to Investigate Early Adenovirus-Host Cell Interactions
2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1863-1882Article in journal (Refereed) Published
Abstract [en]

Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.

Keywords
adenovirus, glycomis, host cell interactions, proteomics, virus entry
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-148152 (URN)10.1016/j.jmb.2018.04.039 (DOI)000436224800004 ()29746851 (PubMedID)2-s2.0-85047296623 (Scopus ID)
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-09-28Bibliographically approved
Westerberg, S., Hagbom, M., Rajan, A., Loitto, V., Persson, D., Allard, A., . . . Svensson, L. (2018). Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells. Journal of Virology, 92(7), Article ID e00026-18.
Open this publication in new window or tab >>Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e00026-18Article in journal (Refereed) Published
Abstract [en]

Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.

Keywords
gastroenteritis, enteric adenovirus, EC cells, serotonin, enteric glia cells
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146907 (URN)10.1128/JVI.00026-18 (DOI)000428409800002 ()29367250 (PubMedID)
Funder
Swedish Research Council, 320301
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-06-27Bibliographically approved
Lenman, A., Liaci, A. M., Liu, Y., Frängsmyr, L., Frank, M., Blaum, B. S., . . . Arnberg, N. (2018). Polysialic acid is a cellular receptor for human adenovirus 52. Proceedings of the National Academy of Sciences of the United States of America, 115(18), E4264-E4273
Open this publication in new window or tab >>Polysialic acid is a cellular receptor for human adenovirus 52
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. E4264-E4273Article in journal (Refereed) Published
Abstract [en]

Human adenovirus 52 (HAdV-52) is one of only three known HAdVs equipped with both a long and a short fiber protein. While the long fiber binds to the coxsackie and adenovirus receptor, the function of the short fiber in the virus life cycle is poorly understood. Here, we show, by glycan microarray analysis and cellular studies, that the short fiber knob (SFK) of HAdV-52 recognizes long chains of α-2,8-linked polysialic acid (polySia), a large posttranslational modification of selected carrier proteins, and that HAdV-52 can use polySia as a receptor on target cells. X-ray crystallography, NMR, molecular dynamics simulation, and structure-guided mutagenesis of the SFK reveal that the nonreducing, terminal sialic acid of polySia engages the protein with direct contacts, and that specificity for polySia is achieved through subtle, transient electrostatic interactions with additional sialic acid residues. In this study, we present a previously unrecognized role for polySia as a cellular receptor for a human viral pathogen. Our detailed analysis of the determinants of specificity for this interaction has general implications for protein-carbohydrate interactions, particularly concerning highly charged glycan structures, and provides interesting dimensions on the biology and evolution of members of Human mastadenovirus G.

Keywords
human adenovirus, short fiber, polysialic acid, glycan receptor, glycan microarray
National Category
Structural Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-147815 (URN)10.1073/pnas.1716900115 (DOI)000431119600017 ()29674446 (PubMedID)
Available from: 2018-05-22 Created: 2018-05-22 Last updated: 2018-06-09Bibliographically 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 University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7069-6678

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