Immunopathogenesis in fungal asthma

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The objective of this competitive renewal R01 is to continue to uncover mechanisms that contribute to the severity of disease in the nearly 40% of severe asthmatics who are sensitized to fungi. Chitin, a polysaccharide found in the fungal cell wall and the exoskeletons of house dust mites and cockroaches, has garnered attention as a potential immunoreactive allergen. Mammals have evolved to express chitin-degrading chitinases (acidic mammalian chitinase and chitotriosidase) and chitin-binding chitinase-like proteins (YKL-40 in humans, BRP-39 in mice) that may modulate immune responses to chitin. Our recently published data demonstrated that chronic fungal exposure in acidic mammalian chitinase (AMCase) deficient mice resulted in lower AHR in the presence of lower type 17 responses (Infect Immun 86:e0094, 2018). These observations prompted the question how can lack of chitin degradation in the absence of AMCase result in better lung function and less inflammation? Put another way, how can putatively higher chitin content in the lung during fungal asthma be beneficial? Based on studies reporting that different chitin particle sizes induced different immune responses, we posited that the generation of some chitin particles in vivo results in responses that regulate rather than promote inflammation. Preliminary data demonstrates that chitin particle sizes (detected by a FITC-labeled chitin binding domain in lung lavage fluid) are different between asthmatic WT and AMCase deficient mice, with some sizes increased and some decreased. Studies in Aim 1 will further examine chitin particle sizes in mice with normal, absent and overexpressed AMCase and correlate these with immune responses that positively or negatively regulate type 17 responses. In other data, mice deficient in the murine homologue of YKL-40 (BRP-39, Chi3l1-/-) demonstrated worse AHR during fungal asthma, despite lower type 2 responses. Bone marrow chimera studies confirmed these findings and demonstrated that BRP-39 expression in either the immune or non-immune compartment resulted in better AHR compared to the dual absence of BRP-39 expression in both compartments. Studies in Aim 2 will further determine immune and non-immune responses modulated by BRP-39 chitin binding. We further show that chronic exposure to pure A. fumigatus chitin results in the induction of type 1 and type 17, but not type 2, responses. Overall, our hypothesis is that during chronic lung exposure to live fungi, AMCase degrades chitin into various sizes, some of which may drive responses that enhance AHR. In contrast, BRP-39 functions to bind chitin, resulting in a response(s) that regulate/reduce AHR. The specific aims of the proposal are: (1) to define mechanisms of AMCase-mediated immunopathogenesis during fungal asthma, (2) to define mechanisms of BRP-39-mediated modulation of fungal asthma severity and (3) to examine chitinase and chitinase-like protein levels in lung samples from human asthmatics sensitized to fungi.