Korwek, Z. | bioRxiv Science

bioRxiv2022

Non-self RNA rewires IFNβ signaling: A mathematical model of the innate immune response

Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which through activation of STAT1/2 in bystander cells induce the expression of IFN-stimulated genes (ISGs). The complex system-level mechanisms of IFN signaling are however not well understood. Here, we show that in cells transfected with an analog of viral RNA, poly(I:C), transcriptional activity of STAT1/2 is terminated due to depletion of the interferon {beta} (IFN{beta}) receptor, IFNAR. Two ISGs, RNase L and PKR, not only hinder replenishment of IFNAR, but also suppress negative regulators of IRF3 and NF-{kappa}B, consequently promoting IFN{beta} transcription. We incorporated these findings into a comprehensive mathematical model of innate immunity. By coupling signaling through the IRF3/NF-{kappa}B and STAT1/2 pathways with the activity of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from STAT1/2-induced to IRF3/NF-{kappa}B-induced, turning IFN{beta}-responding cells to IFN{beta}-secreting cells. One-sentence summaryA computational model explains how non-self RNA turns cells from IFN{beta}- responders to IFN{beta}-producers.

immunology↗

bioRxiv2021

RSV immunizes bystander cells to IAV infection using interferons β and {lambda}

We observed the interference between two prevalent respiratory viruses, respiratory syncytial virus (RSV) and influenza A virus (IAV, H1N1), and characterized its molecular underpinnings in alveolar epithelial cells (A549). We found that RSV induces higher interferon (IFN) {beta} production than IAV and that IFN{beta} priming confers higher protection against infection with IAV than with RSV. Consequently, we focused on the sequential infection scheme: RSV-then-IAV. Using the A549 WT, IFNAR1 KO, IFNLR1 KO, and IFNAR1-IFNLR1 double KO cell lines we found that both IFN{beta} and IFN{lambda} are necessary for maximum protection against subsequent infection. Immunostaining revealed that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. Strikingly, the susceptible cells turned out to be those already compromised and efficiently expressing RSV, whereas the bystander, interferon-primed cells are resistant to IAV infection. Thus, the virus-virus exclusion at the cell population level is not realized through a direct competition for a shared ecological niche (single cell) but rather achieved with the involvement of specific cytokines induced within the host innate immune response. ImportanceThe influenza A virus (IAV) and the respiratory syncytial virus (RSV) are common recurrent respiratory infectants, which show a relatively high coincidence. We demonstrated that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. The susceptible cells are those already compromised and efficiently expressing RSV, whereas the bystander cells are resistant to IAV infection. The cross-protective effect critically depends on IFN{beta} and IFN{lambda} signaling and thus ensues when the proportion of cells preinfected with RSV is relatively low yet sufficient to trigger a pervasive antiviral state in bystander cells. Our study suggests that mild, but not severe, respiratory infections may have a short-lasting protective role against more dangerous respiratory viruses, including SARS-CoV-2.

immunology↗