Experimental evolution identifies an IL-1α dependent host response against Aspergillus fumigatus regulated by the fungal SakA-HOG1 pathway

Abstract Fungal infections are emerging global health threats, costing the United States $7.2 billion annually in health care costs, with Aspergillus fumigatus accounting for $1.2 billion of those costs, the highest for a single fungal species and tied with Candida spp. infections. A. fumigatus has an inexcusably high mortality rate of 40–90%, disproportionately affecting those with compromised immune systems or impaired pulmonary clearance disorders such as CF and COPD. It is critical that the mechanisms behind A. fumigatus pathogenesis is elucidated. In this study, we explore A. fumigatus divergent pathologies amongst multiple strains which induce distinctly different host immune responses based on germination rate. In vivo and in vitro germination of fungal conidia segregate into two distinct groups of “fast” germinators, which elicit an IL-1α dependent host response, and “slow” germinators, which invoke a type I and III interferon dominant response. Here we use experimental evolution to find that the SakA-HOG1 stress response pathway regulates fungal growth in the lung, and serves as a switch for the induction of IL-1α dominant defense. This study demonstrates a need for revision of clinical protocols for treatment of A. fumigatus based on the strain and type of inflammation on-going in patients with A. fumigatus infections as health care standards move toward individualized patient care and antifungal stewardship.