About: MERS-CoV NSP16 necessary for IFN resistance and viral pathogenesis

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About: MERS-CoV NSP16 necessary for IFN resistance and viral pathogenesis Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	MERS-CoV NSP16 necessary for IFN resistance and viral pathogenesis
Creator	Baric, Ralph Gralinski, Lisa Sims, Amy Yount, Boyd Debbink, Kari Menachery, Vineet Mitchell, Hugh Cockrell, Adam Dinnon Iii, Kenneth Graham, Rachel Leist, Sarah Mcanarney, Eileen Stratton, Kelly Waters, Katrina
source	BioRxiv; MedRxiv
abstract	Coronaviruses encode a mix of highly conserved and novel genes as well as genetic elements necessary for infection and pathogenesis, raising the possibility for common targets for attenuation and therapeutic design. In this study, we focus on the highly conserved nonstructural protein (NSP) 16, a viral 2’O methyl-transferase (MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of MERS NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2’O MTase activity had only marginal impact on propagation and replication in Vero cells, the MERS dNSP16 mutant demonstrated significant attenuation relative to control both in primary human airway cultures and in vivo. Further examination indicated the MERS dNSP16 mutant had a type I IFN based attenuation and was partially restored in the absence of IFIT molecules. Importantly, the robust attenuation permitted use of MERS dNSP16 as a live attenuated vaccine platform protecting from challenge with a mouse adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2’O MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. Significance Coronavirus emergence in both human and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of SARS-CoV, MERS-CoV, PEDV and swine delta coronavirus in the 21st century. These studies describe an approach that effectively targets the highly conserved 2’O methyl-transferase activity of coronaviruses for attenuation. With clear understanding of the IFN/IFIT based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-coronavirus functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2’O MTase function across coronaviruses.
has issue date	2017-08-08(xsd:dateTime)
bibo:doi	10.1101/173286
has license	biorxiv
sha1sum (hex)	656ef218f7dcea5555a59cdc29d0f9ec8d5c2a82
schema:url	https://doi.org/10.1101/173286
resource representing a document's title	MERS-CoV NSP16 necessary for IFN resistance and viral pathogenesis
schema:publication	bioRxiv
resource representing a document's body	covid:656ef218f7dcea5555a59cdc29d0f9ec8d5c2a82#body_text
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