PROJECT SUMMARY Fungal pathogens are a serious threat to human health. Invasive pulmonary aspergillosis (IPA) is a severe, life- threatening disease that occurs when Aspergillus fumigatus (AF) spores are inhaled into the respiratory tract and invade airway or lung tissue. More than 200,000 cases of invasive aspergillosis occur each year. A newly identified risk factor for IPA in critically ill patients is influenza infection. Influenza is a common respiratory illness that affects 5-20% of the population each year. Our long-term goal is to develop novel therapeutic interventions for use in clinical settings to prevent morbidity and mortality from IPA. The focus of this application is to identify cell signaling pathways that increase susceptibility to invasive fungal disease following influenza infection. Our preliminary data support that preceding influenza inhibits neutrophil recruitment to the lung, in contrast to post- bacterial pneumonia, and neutropenia is a key risk factor for the development of IPA. Additionally, preceding influenza inhibits neutrophil function against secondary AF infection. Furthermore, our preliminary data demonstrate that the pathogen recognition receptor, CD209a, is decreased in post-influenza IPA, suggesting that preceding influenza may inhibit fungal-sensing. Based on our preliminary data, we hypothesize that preceding influenza A infection limits innate immunity and increases susceptibility to invasive pulmonary aspergillosis by inhibiting CD209a and reducing the host response to secondary Aspergillus fumigatus infection in the lung, including neutrophil recruitment and function. Our research aims include 1) Determine whether neutrophil recruitment and effector functions are inhibited in post-influenza IPA, and 2) Determine whether suppression of CD209a-dependent AF sensing promotes post-influenza IPA. The proposed studies will increase our understanding of how influenza inhibits neutrophil migration to and function within the lung in response to subsequent AF infection (Aim1) and how the immune response to AF is initiated in the lung (Aim 2).