Aspergillus fumigatus strain-specific host response is regulated by glucose sensing.

Abstract

Abstract Our knowledge of how Aspergillus fumigatus growth is controlled within the respiratory tract is developing, but still enigmatic. Recruitment of neutrophils and inflammatory monocytes is critical to control fungal germination. We have recently found that the CEA10 and Af293 strains of A. fumigatus induce unique inflammatory leukocyte responses. Here, we aim to understand why these A. fumigatus strains induce different immune responses and how this affects fungal-induced immunopathology and disease outcome. We used an immunocompetent murine model of invasive pulmonary aspergillosis to evaluate the immune response induced by CEA10 and Af293. We observed that CEA10 undergoes significantly greater germination than Af293, which was regulated by its ability to sense glucose through CreA-mediated signaling. Moreover, the CEA10 strain induced greater lung damage, vascular leakage, and inflammation. These findings suggest the inflammatory response to A. fumigatus might be regulated in a stepwise manner in response to the threat posed by the specific A. fumigatus strain. Specifically, the Af293 strain, which swells but fails to germinate, activates the inflammasome leading to IL-1beta-dependent neutrophil recruitment. In contrast, the CEA10 strain is able to germinate efficiently within the lung, leading to necrotic host cell death, IL-1alpha release, and subsequent IL-1alpha dependent neutrophil recruitment. Clinically, our data support the idea that A. fumigatus strain phenotypic variation may significantly contribute to disease outcomes. Understanding why different A. fumigatus strains induce distinct immune pathology can reveal novel immunotherapeutic targets for the treatment of invasive aspergillosis.