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Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 PLoS+Pathog 2021 ; 17 (8): e1009800 Nephropedia Template TP
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SARS-CoV-2 suppresses IFNbeta production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon #MMPMID34437657
Shemesh M; Aktepe TE; Deerain JM; McAuley JL; Audsley MD; David CT; Purcell DFJ; Urin V; Hartmann R; Moseley GW; Mackenzie JM; Schreiber G; Harari D
PLoS Pathog 2021[Aug]; 17 (8): e1009800 PMID34437657show ga
Type I Interferons (IFN-Is) are a family of cytokines which play a major role in inhibiting viral infection. Resultantly, many viruses have evolved mechanisms in which to evade the IFN-I response. Here we tested the impact of expression of 27 different SARS-CoV-2 genes in relation to their effect on IFN production and activity using three independent experimental methods. We identified six gene products; NSP6, ORF6, ORF7b, NSP1, NSP5 and NSP15, which strongly (>10-fold) blocked MAVS-induced (but not TRIF-induced) IFNbeta production. Expression of the first three of these SARS-CoV-2 genes specifically blocked MAVS-induced IFNbeta-promoter activity, whereas all six genes induced a collapse in IFNbeta mRNA levels, corresponding with suppressed IFNbeta protein secretion. Five of these six genes furthermore suppressed MAVS-induced activation of IFNlambdas, however with no effect on IFNalpha or IFNgamma production. In sharp contrast, SARS-CoV-2 infected cells remained extremely sensitive to anti-viral activity exerted by added IFN-Is. None of the SARS-CoV-2 genes were able to block IFN-I signaling, as demonstrated by robust activation of Interferon Stimulated Genes (ISGs) by added interferon. This, despite the reduced levels of STAT1 and phospho-STAT1, was likely caused by broad translation inhibition mediated by NSP1. Finally, we found that a truncated ORF7b variant that has arisen from a mutant SARS-CoV-2 strain harboring a 382-nucleotide deletion associating with mild disease (Delta382 strain identified in Singapore & Taiwan in 2020) lost its ability to suppress type I and type III IFN production. In summary, our findings support a multi-gene process in which SARS-CoV-2 blocks IFN-production, with ORF7b as a major player, presumably facilitating evasion of host detection during early infection. However, SARS-CoV-2 fails to suppress IFN-I signaling thus providing an opportunity to exploit IFN-Is as potential therapeutic antiviral drugs.
|Adaptor Proteins, Signal Transducing/metabolism[MESH]