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Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity

Journal of virology, 2014-04, Vol.88 (8), p.4251-4264 [Peer Reviewed Journal]

Copyright © 2014, American Society for Microbiology. All Rights Reserved. 2014 American Society for Microbiology ;ISSN: 0022-538X ;EISSN: 1098-5514 ;DOI: 10.1128/jvi.03571-13 ;PMID: 24478444

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Title:
Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity
Author: Menachery, Vineet D ; Yount, Jr, Boyd L ; Josset, Laurence ; Gralinski, Lisa E ; Scobey, Trevor ; Agnihothram, Sudhakar ; Katze, Michael G ; Baric, Ralph S
Dermody, T. S.
Subjects: Adaptor Proteins, Signal Transducing ; Amino Acid Motifs ; Animals ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; DEAD-box RNA Helicases - genetics ; DEAD-box RNA Helicases - metabolism ; Female ; Humans ; Interferon-Induced Helicase, IFIH1 ; Male ; Methyltransferases - chemistry ; Methyltransferases - genetics ; Methyltransferases - metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutation ; Pathogenesis and Immunity ; RNA-Binding Proteins ; SARS coronavirus ; Severe Acute Respiratory Syndrome - genetics ; Severe Acute Respiratory Syndrome - metabolism ; Severe Acute Respiratory Syndrome - virology ; Severe acute respiratory syndrome-related coronavirus - enzymology ; Severe acute respiratory syndrome-related coronavirus - genetics ; Severe acute respiratory syndrome-related coronavirus - pathogenicity ; Severe acute respiratory syndrome-related coronavirus - physiology ; Viral Nonstructural Proteins - chemistry ; Viral Nonstructural Proteins - genetics ; Viral Nonstructural Proteins - metabolism ; Virulence ; Virus Replication
Is Part Of: Journal of virology, 2014-04, Vol.88 (8), p.4251-4264
Description: The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and, more recently, Middle Eastern respiratory syndrome CoV (MERS-CoV) underscores the importance of understanding critical aspects of CoV infection and pathogenesis. Despite significant insights into CoV cross-species transmission, replication, and virus-host interactions, successful therapeutic options for CoVs do not yet exist. Recent identification of SARS-CoV NSP16 as a viral 2'-O-methyltransferase (2'-O-MTase) led to the possibility of utilizing this pathway to both attenuate SARS-CoV infection and develop novel therapeutic treatment options. Mutations were introduced into SARS-CoV NSP16 within the conserved KDKE motif and effectively attenuated the resulting SARS-CoV mutant viruses both in vitro and in vivo. While viruses lacking 2'-O-MTase activity had enhanced sensitivity to type I interferon (IFN), they were not completely restored in their absence in vivo. However, the absence of either MDA5 or IFIT1, IFN-responsive genes that recognize unmethylated 2'-O RNA, resulted in restored replication and virulence of the dNSP16 mutant virus. Finally, using the mutant as a live-attenuated vaccine showed significant promise for possible therapeutic development against SARS-CoV. Together, the data underscore the necessity of 2'-O-MTase activity for SARS-CoV pathogenesis and identify host immune pathways that mediate this attenuation. In addition, we describe novel treatment avenues that exploit this pathway and could potentially be used against a diverse range of viral pathogens that utilize 2'-O-MTase activity to subvert the immune system. Preventing recognition by the host immune response represents a critical aspect necessary for successful viral infection. Several viruses, including SARS-CoV, utilize virally encoded 2'-O-MTases to camouflage and obscure their viral RNA from host cell sensing machinery, thus preventing recognition and activation of cell intrinsic defense pathways. For SARS-CoV, the absence of this 2'-O-MTase activity results in significant attenuation characterized by decreased viral replication, reduced weight loss, and limited breathing dysfunction in mice. The results indicate that both MDA5, a recognition molecule, and the IFIT family play an important role in mediating this attenuation with restored virulence observed in their absence. Understanding this virus-host interaction provided an opportunity to design a successful live-attenuated vaccine for SARS-CoV and opens avenues for treatment and prevention of emerging CoVs and other RNA virus infections.
Publisher: United States: American Society for Microbiology
Language: English
Identifier: ISSN: 0022-538X
EISSN: 1098-5514
DOI: 10.1128/jvi.03571-13
PMID: 24478444
Source: MEDLINE
PubMed Central

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Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity

Copyright © 2014, American Society for Microbiology. All Rights Reserved. 2014 American Society for Microbiology ;ISSN: 0022-538X ;EISSN: 1098-5514 ;DOI: 10.1128/jvi.03571-13 ;PMID: 24478444

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