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Mistry, Nitesh
Publications (3 of 3) Show all publications
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
Zocher, G., Mistry, N., Frank, M., Hähnlein-Schick, I., Ekström, J.-O., Arnberg, N. & Stehle, T. (2014). A sialic acid binding site in a human picornavirus. PLoS Pathogens, 10(10), e1004401
Open this publication in new window or tab >>A sialic acid binding site in a human picornavirus
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2014 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, no 10, p. e1004401-Article in journal (Refereed) Published
Abstract [en]

The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 angstrom resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for alpha 2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that alpha 2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.

Place, publisher, year, edition, pages
Public library science, 2014
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-97242 (URN)10.1371/journal.ppat.1004401 (DOI)000344548800012 ()
Available from: 2014-12-16 Created: 2014-12-12 Last updated: 2018-06-07Bibliographically approved
Mistry, N., Inoue, H., Jamshidi, F., Storm, R. J., Oberste, M. S. & Arnberg, N. (2011). Coxsackievirus A24 variant uses aialic acid-containing O-Linked glycoconjugates as cellular receptors on human ocular cells. Journal of Virology, 85(21), 11283-11290
Open this publication in new window or tab >>Coxsackievirus A24 variant uses aialic acid-containing O-Linked glycoconjugates as cellular receptors on human ocular cells
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2011 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 85, no 21, p. 11283-11290Article in journal (Refereed) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) is a main causative agent of acute hemorrhagic conjunctivitis (AHC), which is a highly contagious eye infection. Previously it has been suggested that CVA24v uses sialic acid-containing glycoconjugates as attachment receptors on corneal cells, but the nature of these receptors is poorly described. Here, we set out to characterize and identify the cellular components serving as receptors for CVA24v. Binding and infection experiments using corneal cells treated with deglycosylating enzymes or metabolic inhibitors of de novo glycosylation suggested that the receptor(s) used by CVA24v are constituted by sialylated O-linked glycans that are linked to one or more cell surface proteins but not to lipids. CVA24v bound better to mouse L929 cells overexpressing human P-selectin glycoprotein ligand-1 (PSGL-1) than to mock-transfected cells, suggesting that PSGL-1 is a candidate receptor for CVA24v. Finally, binding competition experiments using a library of mono- and oligosaccharides mimicking known PSGL-1 glycans suggested that CVA24v binds to Neu5Ac alpha 2,3Gal disaccharides (Neu5Ac is N-acetylneuraminic acid). These results provide further insights into the early steps of the CVA24v life cycle.

Place, publisher, year, edition, pages
Baltimore: American Society for Microbiology, 2011
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-49535 (URN)10.1128/JVI.05597-11 (DOI)000296254400034 ()
Available from: 2011-11-22 Created: 2011-11-14 Last updated: 2018-06-08Bibliographically approved
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