TNF-Mediated Damaging Inflammation During Aspergillus fumigatus Pulmonary Infection is Regulated by Type I Interferon Receptor 2 (IFNAR2)

Abstract Invasive pulmonary aspergillosis (IPA), caused by the fungus Aspergillus fumigatus, generally occurs in patients with suppressed or non-functioning immune systems. The recent increase in the number of cases of influenza and SARS-Cov-2-infected patients acquiring IPA suggests that severe respiratory viral infections may create a suppressed lung immune environment that allows for fungal infections to occur. We recently found that differential type I interferon (IFN) signaling, a classic anti-viral host response, regulates susceptibility to IPA. Specifically, we found that absence of the type I IFN receptor 2 (IFNAR2) subunit of the heterodimeric IFNAR1/2 receptor, leads to increased damage and inflammation in response to A. fumigatus lung infection, while absence of IFNAR1 did not. Although the Ifnar2 −/−mice had higher morbidity, we unexpectedly found that Ifnar2 −/−mice killed more A. fumigatus by 24 hours post-infection compared to WT and Ifnar1 −/−mice. However, this early clearance of A. fumigatus did not prevent invasive disease from developing in the Ifnar2 −/−mice as infection progressed, suggesting that the early damage responses were creating a favorable environment for invasive growth. By altering the inflamed environment of the Ifnar2 −/−mice early during infection, via neutralization of TNFα, we were able to reverse the damage and morbidity in these mice back to WT levels. Further, our results suggest that altered myeloid effector cell responses in Ifnar2 −/−mice during A. fumigatus infection contribute to the damage that occurs. Together, our results expand our understanding of how anti-viral mechanisms, via IFNAR2, are creating a permissive environment for fungal infections to occur through regulation of damage. Supported by grants from NIH/NIGMS (INBRE P20GM103474), NIH/NIAID (K22AI153671), AAI Careers in Immunology Fellowship, Parker B. Francis Fellowship