Heparan Sulfate-Dependent Enhancement of Henipavirus Infection

ABSTRACT Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, th...

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Autores principales:	Cyrille Mathieu, Kévin P. Dhondt, Marie Châlons, Stéphane Mély, Hervé Raoul, Didier Negre, François-Loïc Cosset, Denis Gerlier, Romain R. Vivès, Branka Horvat
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/840d9150e0644ab5aea132d03c6d8d12
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spelling	oai:doaj.org-article:840d9150e0644ab5aea132d03c6d8d122021-11-15T15:41:32ZHeparan Sulfate-Dependent Enhancement of Henipavirus Infection10.1128/mBio.02427-142150-7511https://doaj.org/article/840d9150e0644ab5aea132d03c6d8d122015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02427-14https://doaj.org/toc/2150-7511ABSTRACT Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirus trans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells in vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections. IMPORTANCE The Henipavirus genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells in vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.Cyrille MathieuKévin P. DhondtMarie ChâlonsStéphane MélyHervé RaoulDidier NegreFrançois-Loïc CossetDenis GerlierRomain R. VivèsBranka HorvatAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Cyrille Mathieu Kévin P. Dhondt Marie Châlons Stéphane Mély Hervé Raoul Didier Negre François-Loïc Cosset Denis Gerlier Romain R. Vivès Branka Horvat Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
description	ABSTRACT Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirus trans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells in vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections. IMPORTANCE The Henipavirus genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells in vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.
format	article
author	Cyrille Mathieu Kévin P. Dhondt Marie Châlons Stéphane Mély Hervé Raoul Didier Negre François-Loïc Cosset Denis Gerlier Romain R. Vivès Branka Horvat
author_facet	Cyrille Mathieu Kévin P. Dhondt Marie Châlons Stéphane Mély Hervé Raoul Didier Negre François-Loïc Cosset Denis Gerlier Romain R. Vivès Branka Horvat
author_sort	Cyrille Mathieu
title	Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
title_short	Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
title_full	Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
title_fullStr	Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
title_full_unstemmed	Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
title_sort	heparan sulfate-dependent enhancement of henipavirus infection
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/840d9150e0644ab5aea132d03c6d8d12
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Heparan Sulfate-Dependent Enhancement of Henipavirus Infection

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