Cell-intrinsic regulation of phagocyte function by interferon lambda during pulmonary viral, bacterial super-infection.

Influenza infections result in a significant number of severe illnesses annually, many of which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the host immune response, leading to significant immunopathology. Type III interferons (IFNs), or IFNλs, have gained traction as potential antiviral therapeutics due to their restriction of viral replication without damaging inflammation. The role of IFNλ in regulating epithelial biology in super-infection has recently been established; however, the impact of IFNλ on immune cells is less defined. In this study, we infected wild-type and IFNLR1-/- mice with influenza A/PR/8/34 followed by S. aureus USA300. We demonstrated that global IFNLR1-/- mice have enhanced bacterial clearance through increased uptake by phagocytes, which was shown to be cell-intrinsic specifically in myeloid cells in mixed bone marrow chimeras. We also showed that depletion of IFNLR1 on CX3CR1 expressing myeloid immune cells, but not neutrophils, was sufficient to significantly reduce bacterial burden compared to mice with intact IFNLR1. These findings provide insight into how IFNλ in an influenza-infected lung impedes bacterial clearance during super-infection and show a direct cell intrinsic role for IFNλ signaling on myeloid cells. Author summary: Influenza virus infects millions of people each year and is characterized by a mostly self-resolving mild to moderate illness. However, severe disease is observed in a subset of patients and is often characterized by bacterial super-infection, which occurs following influenza virus infection. In this setting, there can be a lethal synergy between the virus and bacteria that results in severe lung injury. In recent years, the field has determined that type III interferon (IFNλ), induced by influenza virus as part of the anti-viral response, may play a detrimental role during super-infection. This has been attributed to IFNλ impacting structural cells of the airways. In this study, we define a novel role for IFNλ impacting bacterial clearance during super-infection via directly altering lung phagocytes responsible for bacterial host-defense. We use three distinct mouse models to define this new role of IFNλ in regulating phagocyte function in the lung. This study is important because it defines a new mechanism by which anti-viral IFNλ leads to increased susceptibility to bacterial super-infection. This has implications for potential use of IFNλ as an anti-viral therapeutic and identifies a new biologic function of IFNλ in the lung. [ABSTRACT FROM AUTHOR]