Pulmonary Infection with Multiple Strains of Aspergillus fumigatus Reveals a Critical Role for IL-1α Signaling in Host Resistance Against Strains that Rapidly Germinate in the Lungs

Abstract

Abstract Aspergillus fumigatus strain diversity is reflected in heterogeneous virulence and inflammatory responses. Mechanisms underlying A. fumigatus strain specific immune responses and how this affects disease outcome is unresolved. We observe that the CEA10 strain is able to rapidly efficiently within the airway environment and induces greater lung damage, vascular leakage, and IL-1α release compared to the Af293 strain. Fungal clearance is dependent on IL-1α in mice inoculated with the CEA10 strain, while clearance of AF293 does not require IL-1α. Importantly, both swollen conidia and germlings of the CEA10 strain induce robust IL-1α secretion from macrophages in vitro, whereas only germlings of Af293 induce strong production of IL-1α. Our finding that early fungal germination in the airways drives greater pathology and IL-1α dependent inflammation is further supported by similar results with additional strains. First, serial passage of a non-airway germinating strain (Af293) in low-oxygen conditions results in a strain (EVOL20) that germinates more efficiently in the airways leading to enhanced lung damage, vascular leakage, and IL-1α dependent inflammation. Second, using primary clinical and environmental isolates of A. fumigatus that are able to rapidly germinate in airway conditions follows the same trend. Clinically, our data support the idea that A. fumigatus strain phenotypic variation significantly contributes to disease outcomes. Understanding why different A. fumigatus strains induce distinct immune pathology can reveal novel immunotherapeutic and antifungal targets for the treatment of invasive aspergillosis.