The Balance of Interferon-γ and Interleukin-10 during Influenza A Virus Infection Complicated by Methicillin-Resistant Staphylococcus aureus Superinfection

Immune activation is necessary to mount a protective immune response against viral and bacterial infections, but an overzealous response can lead to the development of acute respiratory distress syndrome (ARDS). ARDS is a highly lethal inflammatory lung injury that is associated with dysregulated cytokine production and decreased lung compliance. No specific treatment exists for ARDS due to the limited understanding of its pathogenesis. We have developed an influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) superinfection model with antibiotic therapy that resembles severe secondary bacterial pneumonia in patients that often progresses to ARDS. Despite antibiotic therapy, mice still succumb to superinfection-induced inflammatory lung damage. Using single-cell RNA sequencing, we reveal significant transcriptome alterations prompted by interferon (IFN)-γ. Transgenic mouse studies demonstrate that IFN-γ receptor (IFN-γR) signaling in mononuclear phagocytes induces tumor necrosis factor (TNF)-α hyperproduction and lethal inflammatory lung damage, with no detectable benefit to viral or bacterial clearance. In contrast, we show that interleukin (IL)-10 is crucial to counteract the lethal IFN-γ-induced cytokine storm and preserve lung function. Transgenic mice with ablation of the IL-10 receptor α gene in mononuclear phagocytes have significantly higher levels of IFN-γ and TNF-α, and a higher mortality rate. This reveals the importance of mononuclear phagocytes in shifting the balance between immunopathology and protective immunity. By omitting antibiotic therapy from the superinfection model, we show that IL-10 also impairs bacterial clearance, specifically when the IL-10Rα gene is ablated in interferon-I-responsive monocytes. Collectively, this body of evidence demonstrates the dominant role played by hypercytokinemia and acute lung damage during post-influenza bacterial pneumonia and the balance of IFN-γ and IL-10 that shifts the balance between immunopathogenesis and bacterial outgrowth.