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

Vineet Menachery, Boyd L. Yount, Laurence Josset, Lisa E. Gralinski, Trevor Scobey, Sudhakar Agnihothram, Michael G. Katze, Ralph S. Baric

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4251-4264
Number of pages14
JournalJournal of Virology
Volume88
Issue number8
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Severe Acute Respiratory Syndrome
Coronavirus
methyltransferases
mutants
viruses
live vaccines
interferons
Viruses
therapeutics
pathogenesis
Coronavirus Infections
SARS Virus
Therapeutics
Interferon Type I
Attenuated Vaccines
Virus Replication
infection
Interferons
Virulence
immune system

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity. / Menachery, Vineet; Yount, Boyd L.; Josset, Laurence; Gralinski, Lisa E.; Scobey, Trevor; Agnihothram, Sudhakar; Katze, Michael G.; Baric, Ralph S.

In: Journal of Virology, Vol. 88, No. 8, 01.01.2014, p. 4251-4264.

Research output: Contribution to journalArticle

Menachery, V, Yount, BL, Josset, L, Gralinski, LE, Scobey, T, Agnihothram, S, Katze, MG & Baric, RS 2014, 'Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity', Journal of Virology, vol. 88, no. 8, pp. 4251-4264. https://doi.org/10.1128/JVI.03571-13
Menachery, Vineet ; Yount, Boyd L. ; Josset, Laurence ; Gralinski, Lisa E. ; Scobey, Trevor ; Agnihothram, Sudhakar ; Katze, Michael G. ; Baric, Ralph S. / Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity. In: Journal of Virology. 2014 ; Vol. 88, No. 8. pp. 4251-4264.
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