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Variant specific global loss of cellular m6A RNA methylation during SARS-CoV-2 infection

ABSTRACT: COVID-19 pandemic caused by SARS-CoV-2 is far from getting over because of the emergence of different SARS-CoV-2 variants even though vaccination against SARS-CoV-2 is ongoing. Variant specific mechanistic understanding of host-viral interaction will be required to design novel anti-viral therapeutics. N6-methyladenosine modification (m6A) which is one of the abundant cellular RNA modifications regulates key processes in RNA metabolism during stress response. We observed different SARS-CoV-2 variants during infection causes global loss of m6A in cellular RNA whereas m6A modification was detected abundantly in viral RNA. The loss of m6A in cellular RNAs was more drastic in B.1 and B1.1.7 strains and the main m6A methyltransferase METTL3 shows cytoplasmic localization post-infection. In B1.351 variant effect on METTL3 localization and loss of m6A was less pronounced compared to B.1 and B1.1.7 variants. Gene expression profile suggested changes in RNA catabolism-related pathways including key genes related to m6A readers and erasers during SARS-CoV-2 infection. Genes with m6A peaks were more susceptible to down-regulation during viral infection. Inhibition of export protein XPO1 during infection results in restoration of METTL3 nuclear localization and reduction in viral infection in cell culture suggesting XPO1 inhibition could be an effective therapeutic option for SARS-CoV-2.

ORGANISM(S): Homo sapiens Chlorocebus sabaeus

PROVIDER: GSE188477 | GEO | 2023/02/07

REPOSITORIES: GEO

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Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).

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Variant specific global loss of cellular m6A RNA methylation during SARS-CoV-2 infection

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