Human fungal infections with Aspergillus fumigatus (Af) are becoming more prevalent. Over 4 million cases of Af occur globally, with 300,000 cases/year due to invasive pulmonary aspergillosis in immune suppressed patients. Recent increases in number/severity of cases of influenza and SARS-CoV-2-infected patients acquiring Af suggests that viral infections create suppressed immune environments permissive to fungal infection. Influenza infection was also shown to increase Af susceptibility in mice and was associated with anti-viral type I interferon (IFN) signaling. Importantly, we found that type I IFN signaling, via IFNAR2 of the IFNAR1/2 receptor, contributes to regulation of susceptibility to and damage from influenza in mice, while others have found that IFNAR2 expression correlates with SARS-CoV-2 infection severity. As clinical outcome to Af is associated with host tissue damage, this suggested involvement of IFNAR2 signaling in Af susceptibility. We found that absence of IFNAR2 (Ifnar2−/− mice) resulted in increased damage in the lungs (from myeloid and epithelial/endothelial cells), morbidity, and inflammation in response to Af, while absence of IFNAR1 (Ifnar1−/− mice) did not. We also found that Ifnar2−/− mice developed invasive disease with increased hyphal growth compared to Ifnar1−/− and WT mice and this was associated with epithelial/endothelial damage. Our results also indicate that altered myeloid cell function in Ifnar2−/− mice, rather than differences in cell recruitment, may enhance damage responses and fungal growth. Together, our results begin to establish IFNAR2’s role in regulating host damage responses to Af and suggest that aberrant type I IFN signaling contributes to an Af permissive environment.

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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

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