Séminaire CIRI : Dr. Marco BINDER

Dr. Marco BINDER : " The Winner Takes it All, and COVID19 Likes to Win – Dynamics of Viral Replication vs. Cell-Intrinsic Immunity"

Abstract: We previously observed a primed state of epithelial cells in the upper airway epithelial cells of children prior to infection, characterized by a higher expression level of RLRs, in particular MDA5, as compared to adults (Loske et al., Nat Biotech 2022). This sensitized state was associated with a rapid and robust induction of an IFN signature across epithelial and immune cell types upon SARS-CoV-2 infection. We hence speculate that subtle differences in the set-point of the virus sensing machinery in epithelial cells would have a decisive role in the successful mounting of an IFN response. Here, we report that indeed priming of epithelial A549 cells with low-moderate doses of type I IFN or select inflammatory cytokines sensitizes their RLR pathway sufficiently to produce robust levels of type I and III IFNs upon SARR-CoV-2 infection. We confirm MDA5 as the major sensor, however, we also find a substantial contribution of RIG-I. Wondering why specifically children’s epithelial cells would exhibit this primed state, we looked into the involvement of immune cells. We found microbially stimulated immune cells (PBMCs) of children to be able to induce stronger RLR expression in A549 cells than PBMCs of adults, sufficient to enable a robust IFN induction upon SARS-CoV-2 infection. This immune-epithelial cell interaction was mediated by both type I IFN as well as distinct pro-inflammatory cytokines. Our scRNA-Seq data revealed that this in vitro finding corresponds to the physiological situation, with mucosal immune cells of children exhibiting higher levels of those cytokines at baseline, likely explaining the antiviral priming of their epithelial cells.