Type I IFN Signaling, via IFNb, is involved in regulating antifungal host responses to Aspergillus fumigatus 2260062

Abstract Introduction Invasive pulmonary aspergillosis caused by Aspergillus fumigatus is increasingly common in influenza and SARS-CoV-2 patients, suggesting that antiviral immune responses create susceptibility to fungal infection. We recently demonstrated that differential type I interferon signaling through IFNAR1 vs. IFNAR2 regulates fungal clearance and host damage, respectively, during A. fumigatus infection. Here, we investigated how IFNβ, the strongest IFNAR1/2 activator, regulates these outcomes during infection. Methods We used a murine lung infection model to determine how IFNβ regulates antifungal responses to A. fumigatus via flow cytometry, biochemical assays, and imaging. Results Our preliminary results demonstrate that Ifnβ-/- mice have increased damage, inflammation, and morbidity in response to A. fumigatus infection compared to WT mice. Further, we found that Ifnβ-/- mice are more susceptible to A. fumigatus, demonstrated by decreased survival and increased invasive disease compared to WT mice. We also found that there was no difference in neutrophil cell recruitment to the lungs between Ifnβ-/- and WT mice, suggesting that their anti-fungal responses may be altered. To determine this, we first examined reactive oxygen species (ROS). We found that Ifnβ-/- neutrophils produced increased ROS compared to WT neutrophils in response to both A. fumigatus conidia and hyphae ex vivo. Currently, we are investigating whether ROS directly regulates damage and fungal clearance of the Ifnβ-/- mice in vivo during A. fumigatus infection. Conclusion Here, we demonstrate that IFNβ, like IFNAR2, regulates tissue damage during A. fumigatus infection. Our results suggest IFNβ-mediated regulation of anti-fungal responses contributes to infection susceptibility through damage control. These findings expand our understanding how type I IFN-mediated damage via IFNβ occurs during Aspergillus infections and how antiviral mechanisms create a permissive environment for fungal infection through host damage. Funding Source NIH/NIAD (K22AI153671), Francis Family Foundation, University of California, Merced Start-Up Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)