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

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SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. / Shemesh, Maya; Aktepe, Turgut E.; Deerain, Joshua M. et al.

I: PLOS Pathogens, Bind 17, Nr. 8, e1009800, 08.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

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 2021, 'SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon', PLOS Pathogens, bind 17, nr. 8, e1009800. https://doi.org/10.1371/journal.ppat.1009800

APA

Shemesh, M., Aktepe, T. E., Deerain, J. M., McAuley, J. L., Audsley, M. D., David, C. T., Purcell, D. F. J., Urin, V., Hartmann, R., Moseley, G. W., Mackenzie, J. M., Schreiber, G., & Harari, D. (2021). SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. PLOS Pathogens, 17(8), [e1009800]. https://doi.org/10.1371/journal.ppat.1009800

CBE

Shemesh M, Aktepe TE, Deerain JM, McAuley JL, Audsley MD, David CT, Purcell DFJ, Urin V, Hartmann R, Moseley GW, et al. 2021. SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. PLOS Pathogens. 17(8):Article e1009800. https://doi.org/10.1371/journal.ppat.1009800

MLA

Vancouver

Shemesh M, Aktepe TE, Deerain JM, McAuley JL, Audsley MD, David CT et al. SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. PLOS Pathogens. 2021 aug.;17(8):e1009800. doi: 10.1371/journal.ppat.1009800

Author

Shemesh, Maya ; Aktepe, Turgut E. ; Deerain, Joshua M. et al. / SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. I: PLOS Pathogens. 2021 ; Bind 17, Nr. 8.

Bibtex

@article{8f3d1ca1e0904e7681e5bb4efb776d32,
title = "SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon",
abstract = "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 MAVSinduced 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 = "Maya Shemesh and Aktepe, {Turgut E.} and Deerain, {Joshua M.} and McAuley, {Julie L.} and Audsley, {Michelle D.} and David, {Cassandra T.} and Purcell, {Damian F.J.} and Victoria Urin and Rune Hartmann and Moseley, {Gregory W.} and Mackenzie, {Jason M.} and Gideon Schreiber and Daniel Harari",
note = "Publisher Copyright: {\textcopyright} 2021 Shemesh et al.",
year = "2021",
month = aug,
doi = "10.1371/journal.ppat.1009800",
language = "English",
volume = "17",
journal = "P L o S Pathogens",
issn = "1553-7366",
publisher = "public library of science",
number = "8",

}

RIS

TY - JOUR

T1 - SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon

AU - Shemesh, Maya

AU - Aktepe, Turgut E.

AU - Deerain, Joshua M.

AU - McAuley, Julie L.

AU - Audsley, Michelle D.

AU - David, Cassandra T.

AU - Purcell, Damian F.J.

AU - Urin, Victoria

AU - Hartmann, Rune

AU - Moseley, Gregory W.

AU - Mackenzie, Jason M.

AU - Schreiber, Gideon

AU - Harari, Daniel

N1 - Publisher Copyright: © 2021 Shemesh et al.

PY - 2021/8

Y1 - 2021/8

N2 - 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 MAVSinduced 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.

AB - 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 MAVSinduced 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.

UR - http://www.scopus.com/inward/record.url?scp=85113886042&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1009800

DO - 10.1371/journal.ppat.1009800

M3 - Journal article

C2 - 34437657

AN - SCOPUS:85113886042

VL - 17

JO - P L o S Pathogens

JF - P L o S Pathogens

SN - 1553-7366

IS - 8

M1 - e1009800

ER -