Journal article
Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses
mBio, Vol.9(3), p.e00272-18
05/01/2018
DOI: 10.1128/mBio.00272-18
PMCID: PMC5930304
PMID: 29717007
Abstract
Selective packaging is a mechanism used by multiple virus families to specifically incorporate genomic RNA (gRNA) into virions and exclude other types of RNA. Lineage A betacoronaviruses incorporate a 95-bp stem-loop structure, the packaging signal (PS), into the nsp15 locus of ORF1b that is both necessary and sufficient for the packaging of RNAs. However, unlike other viral PSs, where mutations generally resulted in viral replication defects, mutation of the coronavirus (CoV) PS results in large increases in subgenomic RNA packaging with minimal effects on gRNA packaging and on viral titers. Here, we show that selective packaging is also required for viral evasion of the innate immune response and optimal pathogenicity. We engineered two distinct PS mutants in two different strains of murine hepatitis virus (MHV) that packaged increased levels of subgenomic RNAs, negative-sense genomic RNA, and even cellular RNAs. All PS mutant viruses replicated normally but caused dramatically reduced lethality and weight loss PS mutant virus infection of bone marrow-derived macrophages resulted in increased interferon (IFN) production, indicating that the innate immune system limited the replication and/or pathogenesis of PS mutant viruses PS mutant viruses remained attenuated in MAVS and Toll-like receptor 7-knockout (TLR7 ) mice, two well-known RNA sensors for CoVs, but virulence was restored in interferon alpha/beta receptor-knockout (IFNAR ) mice or in MAVS mice treated with IFNAR-blocking antibodies. Together, these data indicate that coronaviruses promote virulence by utilizing selective packaging to avoid innate immune detection. Coronaviruses (CoVs) produce many types of RNA molecules during their replication cycle, including both positive- and negative-sense genomic and subgenomic RNAs. Despite this, coronaviruses selectively package only positive-sense genomic RNA into their virions. Why CoVs selectively package their genomic RNA is not clear, as disruption of the packaging signal in MHV, which leads to loss of selective packaging, does not affect genomic RNA packaging or virus replication in cultured cells. This contrasts with other viruses, where disruption of selective packaging generally leads to altered replication. Here, we demonstrate that in the absence of selective packaging, the virulence of MHV was significantly reduced. Importantly, virulence was restored in the absence of interferon signaling, indicating that selective packaging is a mechanism used by CoVs to escape innate immune detection.
Details
- Title: Subtitle
- Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses
- Creators
- Jeremiah Athmer - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAAnthony R Fehr - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAMatthew E Grunewald - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAWen Qu - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAD Lori Wheeler - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAKevin W Graepel - Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, USARudragouda Channappanavar - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USAAimee Sekine - Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USADana Saud Aldabeeb - Department of Medicine, King Saud University Medical City, College of Medicine, Riyadh, Saudi ArabiaMichael Gale JrMark R Denison - Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, USAStanley Perlman - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA Stanley-perlman@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.9(3), p.e00272-18
- DOI
- 10.1128/mBio.00272-18
- PMID
- 29717007
- PMCID
- PMC5930304
- NLM abbreviation
- mBio
- ISSN
- 2150-7511
- eISSN
- 2150-7511
- Publisher
- United States
- Grant note
- R01 AI104002 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS T32 GM007347 / NIGMS NIH HHS R01 AI108197 / NIAID NIH HHS F30 AI129229 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS R01 NS036592 / NINDS NIH HHS
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9983777473102771
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