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Frängsmyr, Lars
Publications (10 of 23) Show all publications
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
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
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
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
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: 2019-08-28Bibliographically approved
Spjut, S., Qian, W., Bauer, J., Storm, R., Frängsmyr, L., Stehle, T., . . . Elofsson, M. (2011). A Potent Trivalent Sialic Acid Inhibitor of Adenovirus Type 37 Infection of Human Corneal Cells. Angewandte Chemie International Edition, 50(29), 6519-6521
Open this publication in new window or tab >>A Potent Trivalent Sialic Acid Inhibitor of Adenovirus Type 37 Infection of Human Corneal Cells
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2011 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, no 29, p. 6519-6521Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley, 2011
Keywords
adenoviruses, antiviral agents, crystal-structure elucidation, sialic acids, surface plasmon resonance
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-45043 (URN)10.1002/anie.201101559 (DOI)21648036 (PubMedID)
Available from: 2011-06-22 Created: 2011-06-20 Last updated: 2018-06-08Bibliographically approved
Lenman, A., Mueller, S., Nygren, M. I., Frängsmyr, L., Stehle, T. & Arnberg, N. (2011). Coagulation factor IX mediates serotype-specific binding of species A adenoviruses to host cells. Journal of Virology, 85(24), 13420-13431
Open this publication in new window or tab >>Coagulation factor IX mediates serotype-specific binding of species A adenoviruses to host cells
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2011 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 24, p. 13420-13431Article in journal (Refereed) Published
Abstract [en]

Human species A adenoviruses (HAdVs) comprise three serotypes: HAdV-12, -18, and -31. These viruses are common pathogens and cause systemic infections that usually involve the airways and/or intestine. In immunocompromised individuals, species A adenoviruses in general, and HAdV-31 in particular, cause life-threatening infections. By combining binding and infection experiments, we demonstrate that coagulation factor IX (FIX) efficiently enhances binding and infection by HAdV-18 and HAdV-31, but not by HAdV-12, in epithelial cells originating from the airways or intestine. This is markedly different from the mechanism for HAdV-5 and other human adenoviruses, which utilize coagulation factor X (FX) for infection of host cells. Surface plasmon resonance experiments revealed that the affinity of the HAdV-31 hexon-FIX interaction is higher than that of the HAdV-5 hexon-FX interaction and that the half-lives of these interactions are profoundly different. Moreover, both HAdV-31-FIX and HAdV-5-FX complexes bind to heparan sulfate-containing glycosaminoglycans (GAGs) on target cells, but binding studies utilizing cells expressing specific GAGs and GAG-cleaving enzymes revealed differences in GAG dependence and specificity between these two complexes. These findings add to our understanding of the intricate infection pathways used by human adenoviruses, and they may contribute to better design of HAdV-based vectors for gene and cancer therapy. Furthermore, the interaction between the HAdV-31 hexon and FIX may also serve as a target for antiviral treatment.

Place, publisher, year, edition, pages
Washington: The American Society For Microbiology, 2011
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-50925 (URN)10.1128/JVI.06088-11 (DOI)000297642000058 ()
Available from: 2012-01-20 Created: 2012-01-02 Last updated: 2018-06-08Bibliographically approved
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