IL-1 signaling in defense against Aspergillus fumigatus infection

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PROJECT SUMMARY/ABSTRACT Invasive aspergillosis (IA) is a life-threatening pulmonary infection of immunocompromised patients caused by Aspergillus fumigatus. While previous work has identified recruited phagocytes as critical cellular players in controlling A. fumigatus infection, a major knowledge gap exists regarding the role of lung structural cells in establishing the anti-fungal environment of the lung. My preliminary data indicates that IL-1 receptor (IL-1R1) signaling promotes neutrophil and monocyte killing of A. fumigatus spores (called conidia) and that IL-1R1 expression on lung structural cells is required for production of key anti-fungal cytokines such as GM-CSF. These data strongly suggest an accessory immune role for structural cells during A. fumigatus infection, although the identity of IL-1/-producing cells and IL-1R1-expressing cells is unknown. I hypothesize that production of IL- 1 and  by recruited and lung-resident phagocytes, respectively, is required for optimal immune cell killing of Af conidia and murine survival and that IL-1R1 expression by structural cells is required for broad production of anti-fungal cytokines by diverse structural cell subsets. I will test this hypothesis with the following specific aims: Aim 1: To investigate the cellular sources of IL-1/ and their contributions to prevention of mortality and efficiency of conidial killing in the A. fumigatus-infected lung. I will identify IL-1/ producing cells in infected mouse lungs using ELISAs, flow cytometry, and immunofluorescence microscopy, in both wild-type mice and mice depleted of candidate producer cell types. I will infect mice deficient in IL-1 or  with a fluorescent A. fumigatus reporter to test the contributions of each cytokine to fungal killing and murine survival. Aim 2: To define a map of IL-1 responsive structural cell types that produce key cytokines modulating the quality and quantity of the anti-A. fumigatus immune response. I will identify IL-1R1-expressing structural cell subsets in the lung using flow cytometry and microscopy. I will test the requirement for IL-1R1 on specific cellular subsets for murine survival and fungal killing by using mice with conditional Il1r1 deletion on three different structural cell subsets. I will test whether IL-1R1 on structural cells is required for anti-fungal cytokine production and determine which structural cells may produce these cytokines. Upon conducting these aims, I will determine the structural and immune cells involved in IL-1R1-dependent crosstalk during A. fumigatus infection. These results will advance our understanding of immunity to a medically- important fungal pathogen. I have designed this training plan for broad training in fungal pathogenesis and cellular immunology. The sponsor's laboratory and the host institution are the ideal environment for conducting this training and contribute to a high likelihood of success in both research and other aspects of training.