Interferon Receptor 2 (IFNAR2) Regulates the Host Damage Response During Aspergillus Pulmonary Infection

Abstract

RATIONALE: It is estimated that between four and 8 million people worldwide suffer from respiratory infections caused by the fungus Aspergillus fumigatus (Af). Each year over 300,000 of those cases are due to invasive pulmonary aspergillosis (IPA) in patients with suppressed immune systems. Recent increases in the number and severity of cases of both influenza and COVID19-infected patients acquiring aspergillosis suggests that viral infection can create transiently suppressed immune environments permissive to fungal infection. This is likely because the outcome of IPA is directly related to the severity of lung tissue damage. We recently discovered that differential type I interferon (IFN) signaling, via the IFNAR2 subunit of the IFNAR1/2 heterodimeric receptor, regulates damage responses during pulmonary infection, allowing for an environment permissive to fungal infection. Thus, understanding how IFNAR2 regulates the damage response during pulmonary Af infection will allow us to understand the role of type I IFN signaling in anti-fungal immunity and controlling pulmonary tissue damage. METHODS: Utilizing a murine pulmonary infection model, we identified distinct roles for IFNAR2 and IFNAR1 in regulating both damage and clearance during Af infection. We determined the components and extent of the damage response utilizing proteomic, histological, and molecular approaches. RESULTS: We found that absence of the IFNAR2 subunit (Ifnar2-/-mice) resulted in increased damage biomarkers in the lungs (from both myeloid and epithelial/endothelial compartments), increased morbidity, and increased inflammation in response to Af infection, while absence of IFNAR1 (Ifnar1-/-mice) did not. Additionally, we found that presence of IFNAR2 in either WT or Ifnar1-/-mice correlated with early decreased Af conidia clearance compared to Ifnar2-/-mice, and our results suggest that this requires cell-cell interactions/signaling between pulmonary epithelial and myeloid cells. Importantly, however, we found that as Af infection progressed that Ifnar2-/-mice were not able to prevent invasive hyphal growth, and they experienced increased host epithelial and endothelial damage responses, suggesting that the unregulated damage response in the Ifnar2-/-mice may create a conducive environment for invasive Af disease. CONCLUSIONS: Together, our results begin to establish a role for IFNAR2 in regulation of the host damage response to Af and suggests that aberrant type I IFN signaling may contribute to a permissive environment allowing for Af infection to occur. Understanding the mechanisms involved in IFNAR regulation of damage and anti-fungal immunity could inform design of better treatments aimed at minimizing damage in patients with IPA.