Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection

ABSTRACT Virus binding to the cell surface triggers an array of host responses, including activation of specific signaling pathways that facilitate steps in virus entry. Using mouse polyomavirus (MuPyV), we identified host signaling pathways activated upon virus binding to mouse embryonic fibroblast...

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Autores principales:	Samantha D. O’Hara, Robert L. Garcea
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c2e7db073b5f4b88b9b3296b5ac37bfd
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spelling	oai:doaj.org-article:c2e7db073b5f4b88b9b3296b5ac37bfd2021-11-15T15:50:15ZMurine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection10.1128/mBio.01836-162150-7511https://doaj.org/article/c2e7db073b5f4b88b9b3296b5ac37bfd2016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01836-16https://doaj.org/toc/2150-7511ABSTRACT Virus binding to the cell surface triggers an array of host responses, including activation of specific signaling pathways that facilitate steps in virus entry. Using mouse polyomavirus (MuPyV), we identified host signaling pathways activated upon virus binding to mouse embryonic fibroblasts (MEFs). Pathways activated by MuPyV included the phosphatidylinositol 3-kinase (PI3K), FAK/SRC, and mitogen-activated protein kinase (MAPK) pathways. Gangliosides and α4-integrin are required receptors for MuPyV infection. MuPyV binding to both gangliosides and the α4-integrin receptors was required for activation of the PI3K pathway; however, either receptor interaction alone was sufficient for activation of the MAPK pathway. Using small-molecule inhibitors, we confirmed that the PI3K and FAK/SRC pathways were required for MuPyV infection, while the MAPK pathway was dispensable. Mechanistically, the PI3K pathway was required for MuPyV endocytosis, while the FAK/SRC pathway enabled trafficking of MuPyV along microtubules. Thus, MuPyV interactions with specific cell surface receptors facilitate activation of signaling pathways required for virus entry and trafficking. Understanding how different viruses manipulate cell signaling pathways through interactions with host receptors could lead to the identification of new therapeutic targets for viral infection. IMPORTANCE Virus binding to cell surface receptors initiates outside-in signaling that leads to virus endocytosis and subsequent virus trafficking. How different viruses manipulate cell signaling through interactions with host receptors remains unclear, and elucidation of the specific receptors and signaling pathways required for virus infection may lead to new therapeutic targets. In this study, we determined that gangliosides and α4-integrin mediate mouse polyomavirus (MuPyV) activation of host signaling pathways. Of these pathways, the PI3K and FAK/SRC pathways were required for MuPyV infection. Both the PI3K and FAK/SRC pathways have been implicated in human diseases, such as heart disease and cancer, and inhibitors directed against these pathways are currently being investigated as therapies. It is possible that these pathways play a role in human PyV infections and could be targeted to inhibit PyV infection in immunosuppressed patients.Samantha D. O’HaraRobert L. GarceaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Samantha D. O’Hara Robert L. Garcea Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
description	ABSTRACT Virus binding to the cell surface triggers an array of host responses, including activation of specific signaling pathways that facilitate steps in virus entry. Using mouse polyomavirus (MuPyV), we identified host signaling pathways activated upon virus binding to mouse embryonic fibroblasts (MEFs). Pathways activated by MuPyV included the phosphatidylinositol 3-kinase (PI3K), FAK/SRC, and mitogen-activated protein kinase (MAPK) pathways. Gangliosides and α4-integrin are required receptors for MuPyV infection. MuPyV binding to both gangliosides and the α4-integrin receptors was required for activation of the PI3K pathway; however, either receptor interaction alone was sufficient for activation of the MAPK pathway. Using small-molecule inhibitors, we confirmed that the PI3K and FAK/SRC pathways were required for MuPyV infection, while the MAPK pathway was dispensable. Mechanistically, the PI3K pathway was required for MuPyV endocytosis, while the FAK/SRC pathway enabled trafficking of MuPyV along microtubules. Thus, MuPyV interactions with specific cell surface receptors facilitate activation of signaling pathways required for virus entry and trafficking. Understanding how different viruses manipulate cell signaling pathways through interactions with host receptors could lead to the identification of new therapeutic targets for viral infection. IMPORTANCE Virus binding to cell surface receptors initiates outside-in signaling that leads to virus endocytosis and subsequent virus trafficking. How different viruses manipulate cell signaling through interactions with host receptors remains unclear, and elucidation of the specific receptors and signaling pathways required for virus infection may lead to new therapeutic targets. In this study, we determined that gangliosides and α4-integrin mediate mouse polyomavirus (MuPyV) activation of host signaling pathways. Of these pathways, the PI3K and FAK/SRC pathways were required for MuPyV infection. Both the PI3K and FAK/SRC pathways have been implicated in human diseases, such as heart disease and cancer, and inhibitors directed against these pathways are currently being investigated as therapies. It is possible that these pathways play a role in human PyV infections and could be targeted to inhibit PyV infection in immunosuppressed patients.
format	article
author	Samantha D. O’Hara Robert L. Garcea
author_facet	Samantha D. O’Hara Robert L. Garcea
author_sort	Samantha D. O’Hara
title	Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
title_short	Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
title_full	Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
title_fullStr	Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
title_full_unstemmed	Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection
title_sort	murine polyomavirus cell surface receptors activate distinct signaling pathways required for infection
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/c2e7db073b5f4b88b9b3296b5ac37bfd
work_keys_str_mv	AT samanthadohara murinepolyomaviruscellsurfacereceptorsactivatedistinctsignalingpathwaysrequiredforinfection AT robertlgarcea murinepolyomaviruscellsurfacereceptorsactivatedistinctsignalingpathwaysrequiredforinfection
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Murine Polyomavirus Cell Surface Receptors Activate Distinct Signaling Pathways Required for Infection

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