A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection

ABSTRACT Encephalomyocarditis virus (EMCV) is a picornavirus that produces lytic infections in murine and human cells. Employing a genome-wide CRISPR-Cas9 knockout screen to find host factors required for EMCV infection, we identified a role for ADAM9 in EMCV infection. CRISPR-mediated deletion of A...

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Autores principales:	Lindsey E. Bazzone, Michael King, Christopher R. MacKay, Pyae P. Kyawe, Paul Meraner, Daniel Lindstrom, Joselyn Rojas-Quintero, Caroline A. Owen, Jennifer P. Wang, Abraham L. Brass, Evelyn A. Kurt-Jones, Robert W. Finberg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	a disintegrin and metalloproteinase 9 domain (ADAM9) encephalomyocarditis virus functional genomic screen Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0718071866f9446d8c16a518b045e864
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spelling	oai:doaj.org-article:0718071866f9446d8c16a518b045e8642021-11-15T15:55:13ZA Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection10.1128/mBio.02734-182150-7511https://doaj.org/article/0718071866f9446d8c16a518b045e8642019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02734-18https://doaj.org/toc/2150-7511ABSTRACT Encephalomyocarditis virus (EMCV) is a picornavirus that produces lytic infections in murine and human cells. Employing a genome-wide CRISPR-Cas9 knockout screen to find host factors required for EMCV infection, we identified a role for ADAM9 in EMCV infection. CRISPR-mediated deletion of ADAM9 in multiple human cell lines rendered the cells highly resistant to EMCV infection and cell death. Primary fibroblasts from ADAM9 KO mice were also strongly resistant to EMCV infection and cell death. In contrast, ADAM9 KO and WT cells were equally susceptible to infection with other viruses, including the picornavirus Coxsackie virus B. ADAM9 KO cells failed to produce viral progeny when incubated with EMCV. However, bypassing EMCV entry into cells through delivery of viral RNA directly to the cytosol yielded infectious EMCV virions from ADAM9 KO cells, suggesting that ADAM9 is not required for EMCV replication post-entry. These findings establish that ADAM9 is required for the early stage of EMCV infection, likely for virus entry or viral genome delivery to the cytosol. IMPORTANCE Viral myocarditis is a leading cause of death in the United States, contributing to numerous unexplained deaths in people ≤35 years old. Enteroviruses contribute to many cases of human myocarditis. Encephalomyocarditis virus (EMCV) infection causes viral myocarditis in rodent models, but its receptor requirements have not been fully identified. CRISPR-Cas9 screens can identify host dependency factors essential for EMCV infection and enhance our understanding of key events that follow viral infection, potentially leading to new strategies for preventing viral myocarditis. Using a CRISPR-Cas9 screen, we identified a disintegrin and metalloproteinase 9 domain (ADAM9) as a major factor required for the early stages of EMCV infection in both human and murine infection.Lindsey E. BazzoneMichael KingChristopher R. MacKayPyae P. KyawePaul MeranerDaniel LindstromJoselyn Rojas-QuinteroCaroline A. OwenJennifer P. WangAbraham L. BrassEvelyn A. Kurt-JonesRobert W. FinbergAmerican Society for Microbiologyarticlea disintegrin and metalloproteinase 9 domain (ADAM9)encephalomyocarditis virusfunctional genomic screenMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	a disintegrin and metalloproteinase 9 domain (ADAM9) encephalomyocarditis virus functional genomic screen Microbiology QR1-502
spellingShingle	a disintegrin and metalloproteinase 9 domain (ADAM9) encephalomyocarditis virus functional genomic screen Microbiology QR1-502 Lindsey E. Bazzone Michael King Christopher R. MacKay Pyae P. Kyawe Paul Meraner Daniel Lindstrom Joselyn Rojas-Quintero Caroline A. Owen Jennifer P. Wang Abraham L. Brass Evelyn A. Kurt-Jones Robert W. Finberg A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
description	ABSTRACT Encephalomyocarditis virus (EMCV) is a picornavirus that produces lytic infections in murine and human cells. Employing a genome-wide CRISPR-Cas9 knockout screen to find host factors required for EMCV infection, we identified a role for ADAM9 in EMCV infection. CRISPR-mediated deletion of ADAM9 in multiple human cell lines rendered the cells highly resistant to EMCV infection and cell death. Primary fibroblasts from ADAM9 KO mice were also strongly resistant to EMCV infection and cell death. In contrast, ADAM9 KO and WT cells were equally susceptible to infection with other viruses, including the picornavirus Coxsackie virus B. ADAM9 KO cells failed to produce viral progeny when incubated with EMCV. However, bypassing EMCV entry into cells through delivery of viral RNA directly to the cytosol yielded infectious EMCV virions from ADAM9 KO cells, suggesting that ADAM9 is not required for EMCV replication post-entry. These findings establish that ADAM9 is required for the early stage of EMCV infection, likely for virus entry or viral genome delivery to the cytosol. IMPORTANCE Viral myocarditis is a leading cause of death in the United States, contributing to numerous unexplained deaths in people ≤35 years old. Enteroviruses contribute to many cases of human myocarditis. Encephalomyocarditis virus (EMCV) infection causes viral myocarditis in rodent models, but its receptor requirements have not been fully identified. CRISPR-Cas9 screens can identify host dependency factors essential for EMCV infection and enhance our understanding of key events that follow viral infection, potentially leading to new strategies for preventing viral myocarditis. Using a CRISPR-Cas9 screen, we identified a disintegrin and metalloproteinase 9 domain (ADAM9) as a major factor required for the early stages of EMCV infection in both human and murine infection.
format	article
author	Lindsey E. Bazzone Michael King Christopher R. MacKay Pyae P. Kyawe Paul Meraner Daniel Lindstrom Joselyn Rojas-Quintero Caroline A. Owen Jennifer P. Wang Abraham L. Brass Evelyn A. Kurt-Jones Robert W. Finberg
author_facet	Lindsey E. Bazzone Michael King Christopher R. MacKay Pyae P. Kyawe Paul Meraner Daniel Lindstrom Joselyn Rojas-Quintero Caroline A. Owen Jennifer P. Wang Abraham L. Brass Evelyn A. Kurt-Jones Robert W. Finberg
author_sort	Lindsey E. Bazzone
title	A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
title_short	A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
title_full	A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
title_fullStr	A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
title_full_unstemmed	A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection
title_sort	disintegrin and metalloproteinase 9 domain (adam9) is a major susceptibility factor in the early stages of encephalomyocarditis virus infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0718071866f9446d8c16a518b045e864
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A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection

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