IL-1α is Critical for Resistance Against Highly Virulent Aspergillus fumigatus Isolates.

Heterogeneity amongst Aspergillus fumigatus isolates results in unique virulence potential and inflammatory responses. How these isolates drive specific immune responses and how this affects fungal-induced lung damage and disease outcome is unresolved. We demonstrate that the highly virulent CEA10 strain is able to rapidly germinate within the immune competent lung environment inducing greater lung damage, vascular leakage, and IL-1α release compared to the low virulent Af293 strain that germinates with lower frequency in this environment. Importantly, clearance of CEA10 was consequently dependent on IL-1α in contrast to Af293. Release of IL-1α occurred in a caspase 1/11- and P2XR7-independent mechanism, but was dependent on calpain activity. Our finding that early fungal conidia germination drives greater lung damage and IL-1α dependent inflammation is supported by three independent experimental lines. First, pre-germination of Af293 prior to in vivo challenge drives lung damage and an IL-1α dependent neutrophil response. Second, the virulent EVOL20 strain, derived from Af293, is able to germinate in the airways, leading to enhanced lung damage and IL-1α dependent inflammation and fungal clearance. Third, primary environmental A. fumigatus isolates that rapidly germinate in the airway conditions follow the same trend toward IL-1α dependency. Our data support the hypothesis that A. fumigatus phenotypic variation significantly contributes to disease outcomes.