Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in 2012 as a novel etiological agent of severe respiratory disease in humans. As during infection by other viruses, host sensing of viral double-stranded RNA (dsRNA) induces several antiviral pathways. These includ...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Courtney E. Comar, Stephen A. Goldstein, Yize Li, Boyd Yount, Ralph S. Baric, Susan R. Weiss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	MERS-CoV coronavirus interferon antagonist viral accessory proteins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0a97ea3667ad408cb830e467533a9db1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0a97ea3667ad408cb830e467533a9db1
record_format	dspace
spelling	oai:doaj.org-article:0a97ea3667ad408cb830e467533a9db12021-11-15T15:55:24ZAntagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection10.1128/mBio.00319-192150-7511https://doaj.org/article/0a97ea3667ad408cb830e467533a9db12019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00319-19https://doaj.org/toc/2150-7511ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in 2012 as a novel etiological agent of severe respiratory disease in humans. As during infection by other viruses, host sensing of viral double-stranded RNA (dsRNA) induces several antiviral pathways. These include interferon (IFN), oligoadenylate synthetase (OAS)-RNase L, and protein kinase R (PKR). Coronaviruses, including MERS-CoV, potently suppress the activation of these pathways, inducing only modest host responses. Our study describes the functions of two accessory proteins unique to MERS-CoV and related viruses, NS4a and NS4b, during infection in human airway epithelium-derived A549 cells. NS4a has been previously characterized as a dsRNA binding protein, while NS4b is a 2′,5′-phosphodiesterase with structural and enzymatic similarity to NS2 encoded by mouse hepatitis virus (MHV). We found that deletion of NS4a results in increased interferon lambda (IFNL1) expression, as does mutation of either the catalytic site or nuclear localization sequence of NS4b. All of the mutant viruses we tested exhibited slight decreases in replication. We previously reported that, like MHV NS2, NS4b antagonizes OAS-RNase L, but suppression of IFN is a previously unidentified function for viral phosphodiesterases. Unexpectedly, deletion of NS4a does not result in robust activation of the PKR or OAS-RNase L pathways. Therefore, MERS-CoV likely encodes other proteins that contribute to suppression or evasion of these antiviral innate immune pathways that should be an important focus of future work. This study provides additional insight into the complex interactions between MERS-CoV and the host immune response. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.Courtney E. ComarStephen A. GoldsteinYize LiBoyd YountRalph S. BaricSusan R. WeissAmerican Society for MicrobiologyarticleMERS-CoVcoronavirusinterferon antagonistviral accessory proteinsMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	MERS-CoV coronavirus interferon antagonist viral accessory proteins Microbiology QR1-502
spellingShingle	MERS-CoV coronavirus interferon antagonist viral accessory proteins Microbiology QR1-502 Courtney E. Comar Stephen A. Goldstein Yize Li Boyd Yount Ralph S. Baric Susan R. Weiss Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
description	ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in 2012 as a novel etiological agent of severe respiratory disease in humans. As during infection by other viruses, host sensing of viral double-stranded RNA (dsRNA) induces several antiviral pathways. These include interferon (IFN), oligoadenylate synthetase (OAS)-RNase L, and protein kinase R (PKR). Coronaviruses, including MERS-CoV, potently suppress the activation of these pathways, inducing only modest host responses. Our study describes the functions of two accessory proteins unique to MERS-CoV and related viruses, NS4a and NS4b, during infection in human airway epithelium-derived A549 cells. NS4a has been previously characterized as a dsRNA binding protein, while NS4b is a 2′,5′-phosphodiesterase with structural and enzymatic similarity to NS2 encoded by mouse hepatitis virus (MHV). We found that deletion of NS4a results in increased interferon lambda (IFNL1) expression, as does mutation of either the catalytic site or nuclear localization sequence of NS4b. All of the mutant viruses we tested exhibited slight decreases in replication. We previously reported that, like MHV NS2, NS4b antagonizes OAS-RNase L, but suppression of IFN is a previously unidentified function for viral phosphodiesterases. Unexpectedly, deletion of NS4a does not result in robust activation of the PKR or OAS-RNase L pathways. Therefore, MERS-CoV likely encodes other proteins that contribute to suppression or evasion of these antiviral innate immune pathways that should be an important focus of future work. This study provides additional insight into the complex interactions between MERS-CoV and the host immune response. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.
format	article
author	Courtney E. Comar Stephen A. Goldstein Yize Li Boyd Yount Ralph S. Baric Susan R. Weiss
author_facet	Courtney E. Comar Stephen A. Goldstein Yize Li Boyd Yount Ralph S. Baric Susan R. Weiss
author_sort	Courtney E. Comar
title	Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
title_short	Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
title_full	Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
title_fullStr	Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
title_full_unstemmed	Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
title_sort	antagonism of dsrna-induced innate immune pathways by ns4a and ns4b accessory proteins during mers coronavirus infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0a97ea3667ad408cb830e467533a9db1
work_keys_str_mv	AT courtneyecomar antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection AT stephenagoldstein antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection AT yizeli antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection AT boydyount antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection AT ralphsbaric antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection AT susanrweiss antagonismofdsrnainducedinnateimmunepathwaysbyns4aandns4baccessoryproteinsduringmerscoronavirusinfection
_version_	1718427196247244800

Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection

Ejemplares similares