SARS-CoV-2 Uses Nonstructural Protein 16 to Evade Restriction by IFIT1 and IFIT3

Abstract

Understanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2′-O methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process. Based on observations with other CoVs, we hypothesized that NSP16 2′-O MTase function protects SARS-CoV-2 from cap-sensing host restriction. Therefore, we engineered SARS-CoV-2 with a mutation that disrupts a conserved residue in the active site of NSP16. We subsequently show that this mutant is attenuated both in vitro and in vivo, using a hamster model of SARS-CoV-2 infection. Mechanistically, we confirm that the NSP16 mutant is more sensitive to type I interferon (IFN-I) in vitro. Furthermore, silencing IFIT1 or IFIT3, IFN-stimulated genes that sense a lack of 2′-O methylation, partially restores fitness to the NSP16 mutant. Finally, we demonstrate that sinefungin, a methyltransferase inhibitor that binds the catalytic site of NSP16, sensitizes wild-type SARS-CoV-2 to IFN-I treatment. Overall, our findings highlight the importance of SARS-CoV-2 NSP16 in evading host innate immunity and suggest a possible target for future antiviral therapies.

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

“…IFIT proteins are induced by IFN, viral infection, or PAMP recognition, where they can then directly bind to viral RNA, block viral translation, and activate cellular antiviral responses [ 44 ]. A recent preprint found the SARS-CoV-2 nonstructural protein NSP16 helps SARS-CoV-2 evade the host antiviral immune response by avoiding the antiviral activities of IFIT1 and 3 [ 45 ]. MX proteins are interferon-induced dynamin-like GTPases with antiviral activity against multiple RNA and DNA viruses.…”

Study on potential differentially expressed genes in idiopathic pulmonary fibrosis by bioinformatics and next generation sequencing data analysis

“…Altered expression of genes include CX3CR1 [666], S100A12 [667], CSF2 [668], MPO (myeloperoxidase) [669], CD5L [670], F11 [671], S100A8 [672], PGLYRP1 [673], VEGFD (vascular endothelial growth factor D) [674], CXCL11 [373], BPI (bactericidal permeability increasing protein) [675], CXCL10 [676], S100A9 [677], CXCR1 [678], CXCR2 [679], ABCA3 [680], CD36 [681], SHH (sonic hedgehog signaling molecule) [682], TLR3 [683], CLEC4D [684], CCR2 [685], NEK7 [686], TLR7 [687], CCRL2 [688] and CAV1 [689] accelerates pneumonia progression. CX3CR1 [666], CD177 [690], PF4 [691], FFAR2 [692], MPO (myeloperoxidase) [693], F11 [694], S100A8 [695], VEGFD (vascular endothelial growth factor D) [674], IL1A [696], BPI (bactericidal permeability increasing protein) [697], AQP4 [698], BDNF (brain derived neurotrophic factor) [699], CXCL10 [700], RNASE2 [701], FCGR3B [702], S100A9 [703], IL1B [704], CXCR2 [705], GPIHBP1 [294], CD36 [706], TRIB3 [707], PCSK9 [708], FGF2 [709], FASN (fatty acid synthase) [710], PNPLA3 [711], HSPA6 [712], VIP (vasoactive intestinal peptide) [713], TLR3 [683], ADRB1 [328], SPOCK2 [714], TLR8 [715], CCR2 [716], IFIT3 [71...…”

Reference-quality bat genomes illuminate adaptations to viral tolerance and disease resistance

“…IFNB1 and other type I interferons activate the JAK-STAT cascade that induces interferon-stimulated genes such as IFIT2 (also called ISG54), IFIT3 (ISG60), and ISG15. IFIT2 (selected in C) and IFIT3 (selected in R) encode cytoplasmic proteins that restrict replication of corona-and many other viruses by sensing viral mRNAs and inhibiting their translation [76][77][78][79] . ISG15 is an antiviral protein that lacks a key Cysteine residue in rhinolophid and hipposiderid bats which is required for homodimer formation (investigated in detail below).…”