Distinct type I interferon (IFN) signaling is involved in damage and fungal clearance during <i>Aspergillus</i> pulmonary infection

Abstract 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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