Paradoxical role of IL-10 during influenza A virus and MRSA coinfection

Abstract Acute respiratory distress syndrome (ARDS) is a highly lethal inflammatory lung injury characterized by an excessive and dysregulated cytokine response. Viral or bacterial pneumonia is the most common cause of ARDS, but the events that trigger hypercytokinemia are unclear. Thus, no ARDS mechanism-specific treatments exist. Secondary methicillin-resistant Staphylococcus aureus (MRSA) pneumonia has contributed significantly to morbidity and mortality in recent influenza pandemics. By using a mouse model of influenza A virus (IAV) and MRSA coinfection, we have shown that IAV infection inhibits phagocyte oxidative burst-dependent MRSA clearance but nevertheless lethal oxidative lung damage ensues following MRSA infection. Cytokines regulate the balance between immune protection and immunopathology. Accordingly, we have shown that an IFN-γ and TNF-α dominant cytokine storm promotes lethal lung inflammation following IAV/MRSA coinfection. IL-10 is a potent anti-inflammatory cytokine; it counteracts many biological effects of IFN-γ. Therefore, we hypothesize that IL-10 is required to limit lung immunopathology during IAV/MRSA coinfection. Indeed, we found that IL-10-deficient mice are highly susceptible to coinfection, correlating with their IFN-γ hyperproduction. Interestingly, mice lacking IL-10 receptor alpha in myeloid cells (Lyz2 CreIl0ra fl/fl) are also highly susceptible to coinfection, despite their improved bacterial clearance. This increased susceptibility is associated with hyperproduction of inflammatory cytokines. Ongoing studies will examine the impact of IL-10 on neutrophils and mononuclear phagocytes to elucidate their respective contribution to bacterial clearance and immunopathology. R01 HL118408