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Arnberg, Niklas
Publications (10 of 47) Show all publications
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
Baggen, J., Hurdiss, D. L., Zocher, G., Mistry, N., Roberts, R. W., Slager, J. J., . . . van Kuppeveld, F. J. M. (2018). Role of enhanced receptor engagement in the evolution of a pandemic acute hemorrhagic conjunctivitis virus. Proceedings of the National Academy of Sciences of the United States of America, 115(2), 397-402
Open this publication in new window or tab >>Role of enhanced receptor engagement in the evolution of a pandemic acute hemorrhagic conjunctivitis virus
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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 2, p. 397-402Article in journal (Refereed) Published
Abstract [en]

Acute hemorrhagic conjunctivitis (AHC) is a painful, contagious eye disease, with millions of cases in the last decades. Coxsackievirus A24 (CV-A24) was not originally associated with human disease, but in 1970 a pathogenic "variant" (CV-A24v) emerged, which is now the main cause of AHC. Initially, this variant circulated only in Southeast Asia, but it later spread worldwide, accounting for numerous AHC outbreaks and two pandemics. While both CV-A24 variant and nonvariant strains still circulate in humans, only variant strains cause AHC for reasons that are yet unknown. Since receptors are important determinants of viral tropism, we set out to map the CV-A24 receptor repertoire and establish whether changes in receptor preference have led to the increased pathogenicity and rapid spread of CV-A24v. Here, we identify ICAM-1 as an essential receptor for both AHC-causing and non-AHC strains. We provide a high-resolution cryo-EM structure of a virus-ICAM-1 complex, which revealed critical ICAM-1-binding residues. These data could help identify a possible conserved mode of receptor engagement among ICAM-1-binding enteroviruses and rhinoviruses. Moreover, we identify a single capsid substitution that has been adopted by all pandemic CV-A24v strains and we reveal that this adaptation enhances the capacity of CV-A24v to bind sialic acid. Our data elucidate the CV-A24v receptor repertoire and point to a role of enhanced receptor engagement in the adaptation to the eye, possibly enabling pandemic spread.

Place, publisher, year, edition, pages
National Academy of Sciences, 2018
Keywords
conjunctivitis, coxsackievirus A24v, receptor, ICAM-1, sialic acid
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-144398 (URN)10.1073/pnas.1713284115 (DOI)000419686400061 ()29284752 (PubMedID)
Available from: 2018-02-13 Created: 2018-02-13 Last updated: 2018-06-09Bibliographically approved
Storm, R. J., Persson, D. B., Skalman, L. N., Frängsmyr, L., Lindström, M., Rankin, G., . . . Arnberg, N. (2017). Human Adenovirus Type 37 Uses αVβ1 and α3β1 Integrins for Infection of Human Corneal Cells. Journal of Virology, 91(5), Article ID e02019-16.
Open this publication in new window or tab >>Human Adenovirus Type 37 Uses αVβ1 and α3β1 Integrins for Infection of Human Corneal Cells
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2017 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 91, no 5, article id e02019-16Article in journal (Refereed) Published
Abstract [en]

Epidemic keratoconjunctivitis (EKC) is a severe, contagious ocular disease that affects 20 to 40 million individuals worldwide every year. EKC is mainly caused by six types of human adenovirus (HAdV): HAdV-8, -19, -37, -53, -54, and -56. Of these, HAdV-8, -19, and -37 use sialic acid-containing glycans as cellular receptors. αVβ3, αVβ5, and a few additional integrins facilitate entry and endosomal release of other HAdVs. With the exception of a few biochemical analyses indicating that HAdV-37 can interact physically with αVβ5, little is known about the integrins used by EKC-causing HAdVs. Here, we investigated the overall integrin expression on human corneal cells and found expression of α2, α3, α6, αV, β1, and β4 subunits in human corneal in situ epithelium and/or in a human corneal epithelial (HCE) cell line but no or less accessible expression of α4, α5, β3, or β5. We also identified the integrins used by HAdV-37 through a series of binding and infection competition experiments and different biochemical approaches. Together, our data suggest that HAdV-37 uses αVβ1 and α3β1 integrins for infection of human corneal epithelial cells. Furthermore, to confirm the relevance of these integrins in the HAdV-37 life cycle, we developed a corneal multilayer tissue system and found that HAdV-37 infection correlated well with the patterns of αV, α3, and β1 integrin expression. These results provide further insight into the tropism and pathogenesis of EKC-causing HAdVs and may be of importance for future development of new antiviral drugs.IMPORTANCE Keratitis is a hallmark of EKC, which is caused by six HAdV types (HAdV-8, -19, -37, -53, -54, and -56). HAdV-37 and some other HAdV types interact with integrin αVβ5 in order to enter nonocular human cells. In this study, we found that αVβ5 is not expressed on human corneal epithelial cells, thus proposing other host factors mediate corneal infection. Here, we first characterized integrin expression patterns on corneal tissue and corneal cells. Among the integrins identified, competition binding and infection experiments and biochemical assays pointed out αVβ1 and α3β1 to be of importance for HAdV-37 infection of corneal tissue. In the absence of a good animal model for EKC-causing HAdVs, we also developed an in vitro system with multilayer HCE cells and confirmed the relevance of the suggested integrins during HAdV-37 infection.

Keywords
adenoviruses, cornea, epidemic keratoconjunctivitis, integrins
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-133501 (URN)10.1128/JVI.02019-16 (DOI)000394356400016 ()27974569 (PubMedID)
Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2018-08-06Bibliographically approved
Kaján, G. L., Kajon, A. E., Pinto, A. C., Bartha, D. & Arnberg, N. (2017). The complete genome sequence of human adenovirus 84, a highly recombinant new Human mastadenovirus D type with a unique fiber gene. Virus Research, 242, 79-84
Open this publication in new window or tab >>The complete genome sequence of human adenovirus 84, a highly recombinant new Human mastadenovirus D type with a unique fiber gene
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2017 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 242, p. 79-84Article in journal (Refereed) Published
Abstract [en]

A novel human adenovirus was isolated from a pediatric case of acute respiratory disease in Panama City, Panama in 2011. The clinical isolate was initially identified as an intertypic recombinant based on hexon and fiber gene sequencing. Based on the analysis of its complete genome sequence, the novel complex recombinant Human mastadenovirus D (HAdV-D) strain was classified into a new HAdV type: HAdV-84, and it was designated Adenovirus D human/PAN/P309886/2011/84[P43H17F84]. HAdV-D types possess usually an ocular or gastrointestinal tropism, and respiratory association is scarcely reported. The virus has a novel fiber type, most closely related to, but still clearly distant from that of HAdV-36. The predicted fiber is hypothesised to bind sialic acid with lower affinity compared to HAdV-37. Bioinformatic analysis of the complete genomic sequence of HAdV-84 revealed multiple homologous recombination events and provided deeper insight into HAdV evolution.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Human adenovirus, Complete genome, HAdV-84, Homologous recombination, HAdV-D, Acute respiratory disease
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-142911 (URN)10.1016/j.virusres.2017.09.012 (DOI)000415777800011 ()28923509 (PubMedID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-06-09Bibliographically approved
Lenman, A., Liaci, A. M., Liu, Y., Årdahl, C., Rajan, A., Nilsson, E., . . . Arnberg, N. (2015). Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells. PLoS Pathogens, 11(2), Article ID e1004657.
Open this publication in new window or tab >>Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells
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2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 2, article id e1004657Article in journal (Refereed) Published
Abstract [en]

Most adenoviruses attach to host cells by means of the protruding fiber protein that binds to host cells via the coxsackievirus and adenovirus receptor (CAR) protein. Human adenovirus type 52 (HAdV-52) is one of only three gastroenteritis-causing HAdVs that are equipped with two different fiber proteins, one long and one short. Here we show, by means of virion-cell binding and infection experiments, that HAdV-52 can also attach to host cells via CAR, but most of the binding depends on sialylated glycoproteins. Glycan microarray, flow cytometry, surface plasmon resonance and ELISA analyses reveal that the terminal knob domain of the long fiber (52LFK) binds to CAR, and the knob domain of the short fiber (52SFK) binds to sialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complex with 2-O-methylated sialic acid combined with functional studies of knob mutants revealed a new sialic acid binding site compared to other, known adenovirus: glycan interactions. Our findings shed light on adenovirus biology and may help to improve targeting of adenovirus-based vectors for gene therapy.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-103565 (URN)10.1371/journal.ppat.1004657 (DOI)000352083400038 ()25674795 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-21 Last updated: 2018-06-07Bibliographically approved
Caraballo, R., Saleeb, M., Bauer, J., Liaci, A.-M., Chandra, N., Storm, R. J., . . . Elofsson, M. (2015). Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells. Organic and biomolecular chemistry, 13(35), 9194-9205
Open this publication in new window or tab >>Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells
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2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 35, p. 9194-9205Article in journal (Refereed) Published
Abstract [en]

Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-100014 (URN)10.1039/C5OB01025J (DOI)000360115100007 ()
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2018-06-07Bibliographically approved
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