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MBio. 2019 Feb 5;10(1). pii: e02734-18. doi: 10.1128/mBio.02734-18.

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

Author information

1
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
2
Department of Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
4
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
6
Peak Gastroenterology Associates, Colorado Springs, Colorado, USA.
7
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA Evelyn.Kurt-Jones@umassmed.edu Robert.Finberg@umassmed.edu.
#
Contributed equally

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.

KEYWORDS:

a disintegrin and metalloproteinase 9 domain (ADAM9); encephalomyocarditis virus; functional genomic screen

PMID:
30723129
PMCID:
PMC6428755
DOI:
10.1128/mBio.02734-18
[Indexed for MEDLINE]
Free PMC Article

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