Journal Article

SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon

Purcell, Damian F. J., Deerain, Joshua M., McAuley, Julie L., Aktepe, Turgut E., Mackenzie, Jason M., David, Cassandra T., Harari, Daniel, Schreiber, Gideon, Urin, Victoria, Shemesh, Maya, Moseley, Gregory W., Audsley, Michelle D., Hartmann, Rune

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Adaptor Proteins, Vesicular Transport - metabolism / Animals / Biology and life sciences / Chlorocebus aethiops / Eukaryotic Initiation Factor-2 - metabolism / HEK293 Cells / Humans / Interferon-beta - genetics / Interferon-beta - metabolism / Interferon-beta - pharmacology / Medicine and health sciences / Research and Analysis Methods / SARS-CoV-2 - drug effects / SARS-CoV-2 - immunology / STAT1 Transcription Factor - metabolism / Vero Cells / Viral Proteins - genetics / Viral Proteins - metabolism