Complement C3 promotes protective pulmonary antifungal response 9295

Abstract Description Invasive pulmonary aspergillosis (IPA) is a deadly fungal infection caused by the environmental fungus Aspergillus fumigatus with annual mortality rates exceeding 40% globally despite concurrent antifungal treatment. IPA is a serious complication in patients with quantitative and qualitative defects of myeloid phagocytes. Recent occurrence of IPA in patients on complement-targeting therapies, highlighting the protective roles of C3. Complement protein C3 plays critical roles in systemic antifungal host defense, but its functions and regulation for protection during IPA remains elusive. Our data indicate an essential role for C3 in protection during IPA, as C3-deficient mice are highly susceptible to IPA. In addition, pulmonary C3, rather than liver-derived serum C3, is vital for IPA defense. We identified recruited neutrophils, Ly6Chi inflammatory monocytes, monocyte-derived dendritic cells, alveolar macrophages, and lung stroma as sources of pulmonary C3. Notably, we observed cell autonomous C3 to be necessary for fungal killing by myeloid phagocytes, not for leukocyte accumulation. Furthermore, our results highlighting a prominent role for the larger C3 fragment C3b/iC3b in protection, potentially via signaling through the cognate receptors - CR3 and CD46. Our ongoing work is aimed at uncovering novel C3-mediated pulmonary antifungal defense mechanisms. These insights will improve patient outcomes by informing risk stratification for those on complement-targeted therapies. Funding Sources K99/R00 award from NIAID (4R00AI141622) to Jigar V Desai Topic Categories Immune Mechanisms of Human Disease (HUM)