Abstract
Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions.
Highlights
Influenza A virus (IAV) is a leading cause of respiratory infection and an ongoing threat to global health
Influenza A virus (IAV) is a leading cause of respiratory infection and induces a strong acute inflammation manifested by the recruitment of monocytes and neutrophils as well as the production of proinflammatory cytokines in infected lungs
We demonstrate that anti-viral IFN signaling is required for the orchestration of a tissue response associated with the protection against IAV infection in mice
Summary
Influenza A virus (IAV) is a leading cause of respiratory infection and an ongoing threat to global health. Recent studies have suggested that the host immune response rather than the cytopathic effect of viral infection plays the key role in driving tissue pathology and host mortality [3,4,5]. IAV triggers an acute pulmonary inflammation associated with the recruitment of inflammatory monocytes and neutrophils in infected lungs (reviewed in [6]). While it is clear that elevated neutrophil accumulation into infected lungs is associated with increased mortality following IAV infection [7,8], monocyte recruitment can be host protective or detrimental [9,10], suggesting that monocytes may play a multifactorial role in the infection. The classical Ly6Chi monocytes are known to mediate various inflammatory conditions [12] and accumulate in large numbers in IAV-infected lungs [13]. The phenotype and function of Ly6Clo monocytes / macrophages (Mo/Mφ) in IAV infection are currently unknown
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