부산대학교 도서관

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) IFNβ production. Expression of the first three of these SARS-CoV-2 genes specifically blocked MAVS-induced IFNβ-promoter activity, whereas all six genes induced a collapse in IFNβ mRNA levels, corresponding with suppressed IFNβ protein secretion. Five of these six genes furthermore suppressed MAVS-induced activation of IFNλs, however with no effect on IFNα or IFNγ 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 (Δ382 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. Author summary: Our immune system provides the first-line of defense to combat viral infection through the localized triggering of Type I Interferons (IFN-Is). This is a family of cytokines which send a localized "red alert" signal to both infected and adjacent cells, activating hundreds of antiviral genes thus triggering a major arm of innate immunity. So important are IFN-Is, that it is perhaps not surprising that many viruses have evolved mechanisms to block the triggering of IFN-I production and sometimes to additionally block IFN-I signaling. Herein we have demonstrated that SARS-CoV-2, the virus responsible for COVID19, harbors six genes that block the production of IFNβ, a major subtype of IFN-Is. However, even though SARS-CoV-2 infection had the capacity to strongly decrease pSTAT1, a lynchpin molecule required to disseminate IFN-I signaling, enough residual pSTAT1 remained to allow activation of the anti-viral program. Our findings demonstrate that this coronavirus has devoted a significant proportion of its genome to block IFN-I production, presumably in order to help it establish early stage infection. Nevertheless, this virus remains sensitive to the effects of added interferon, providing an opportunity to treat COVID19 patients with IFN-Is therapeutically. [ABSTRACT FROM AUTHOR]