RSV protects bystander cells against IAV infection by triggering secretion of type I and type III interferons

Abstract

AbstractWe 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) β production than IAV and that IFNβ 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 IFNβ and IFNλ 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 IFNβ and IFNλ 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.</jats:sec