SUMMARY Pneumonia, caused by bacterial and/or viral etiology, is the leading cause of death in children worldwide. Preceding viral illness, linked to influenza infection, is a primary risk factor associated with secondary bacterial pneumonia. Influenza infection is an annual, seasonal cause of morbidity and mortality throughout the world. Severe influenza pneumonia is often exacerbated by bacterial infection resulting in poor patient outcomes even in previously healthy individuals. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence and is now more common than Streptococcus pneumoniae, the previously predominant pathogen. The lack of effective anti-viral therapeutics, immunomodulatory drugs, and increasing antibiotic resistance, coupled with poor vaccine coverage and efficacy, results in a dire need for novel therapeutic target identification. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during seasonal and pandemic outbreaks. During the previous funding periods, our laboratory has identified suppression of bacterial-induced Type 17 immune responses by preceding influenza as a critical susceptibility mechanism. We have published extensively in this area, elucidating aberrant host defense pathways in this context. In this application, we will build upon our ongoing work with two highly novel Aims derived from the original focus. We now provide preliminary data implicating a detrimental role for type III interferon (IFNλ) in super-infection through inhibiting monocyte function and pattern recognition receptor expression. These data support the hypothesis that influenza induced IFNλ directly inhibits monocyte antibacterial function via suppression of SIGNR3/4, which is required for subsequent activation of Type 17 immunity and S. aureus clearance during super-infection. In Aim 1, we will determine the mechanism by which IFNλ inhibits monocyte function during influenza, S. aureus super-infection. In Aim 2, we will define the role of SIGNR3/4 in host defense against S. aureus in the lung. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1) and how the immune response to influenza attenuate S. aureus clearance in the lung (Aim 2). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super-infection and identify novel treatment targets in a pre-clinical model of disease.