Interferon Receptor 2 (IFNAR2) is involved in regulation of host damage responses and fungal clearance during <i>Aspergillus fumigatus</i> pulmonary infection

Abstract Three million people globally suffer from infections caused by Aspergillus fumigatus (Af). Over 300,000 of these cases are due to invasive pulmonary aspergillosis (IPA) in patients with suppressed immune systems. The recent increase of aspergillosis in influenza-infected patients suggests that influenza infection creates transiently suppressed immune environments permissive to fungal infection. Consistent with this, we found that influenza infected WT mice had increased Af lung fungal burden and cellular damage compared to Af-only infected mice. We recently discovered that type I interferon (IFN) signaling, via IFNAR2 of the IFNAR1/2 receptor, regulates susceptibility to and damage from influenza. A main factor contributing to IPA pathology and outcome is the level of damage the host incurs. Importantly, we found that IFNAR2 deficiency (Ifnar2−/− mice) resulted in increased cellular damage and morbidity at 24 hrs post-Af compared to WT and Ifnar1−/− mice. Interestingly, Ifnar2−/− mice cleared spores more efficiently than both WT and Ifnar1−/− mice but were unable to control invasive disease and maintain pulmonary architecture, evidenced by hyphal growth and fibrosis-like tissue at 48 hrs post-Af. Although cellular recruitment was unaltered, the levels of inflammatory cytokines in Ifnar2−/− mice was two-fold higher than WT and Ifnar1−/− mice, and Ifnar2−/− neutrophils produced more external ROS in response to Af suggesting altered effector cell function may be involved in the IFNAR2 regulated damage response. Together, our results begin to establish a role for IFNAR2 in regulation of the host damage response to Af and suggest that aberrant type I IFN signaling creates a permissive environment allowing for Af infection to occur.

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