Type I IFN Signaling Controls Damage and Clearance During Pulmonary Aspergillus Fumigatus Infection

RATIONALE: Recently, there has been an increased incidence of invasive pulmonary aspergillosis (IPA), caused by the human fungal pathogen Aspergillus fumigatus (Af), occurring in patients infected with influenza or SARS-CoV-2. Along with the recently described involvement of type I interferon (IFN) signaling in increased Af susceptibility during viral infection in mice, this strongly indicates that anti-viral immune responses, such as type I IFNs, create an environment permissive to fungal infection. Supporting this, we found that type I IFN signaling, via the type I IFN receptor 2 (IFNAR2) of IFNAR1/2, 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 suggests that IFNAR2's regulation of damage response during pulmonary infection may control the immune status of the lung, via tissue damage, allowing for fungal infection to occur. METHODS: We are utilizing a murine pulmonary infection model, to identify distinct roles for IFNAR2 and IFNAR1 and type I IFN signaling in regulating both damage and clearance during IPA. We employed proteomic, histological, and molecular approaches to determine the components and extent of the damage response. RESULTS: We found that absence of IFNAR2 (Ifnar2-/- mice) resulted in increased damage, weight loss, and morbidity early during Af infection compared to WT and Ifnar1-/- mice. Additionally, we also found that both WT and Ifnar1-/- mice had decreased Af clearance early during infection compared to Ifnar2-/- mice and that this difference in killing of Af required in vivo interactions/signaling. However, as Af infection progressed we found that although Ifnar2-/- mice cleared Af early, this did not prevent invasive hyphal growth from occurring. This invasive growth in the Ifnar2-/- mice was found to be associated with increased damage and cell death in the Af lesions within the lung. Importantly, our results suggest that this IFNAR2 damage response is being mediated by distinct type I IFNs, specifically IFNβ. CONCLUSIONS: Together, our results begin to establish a role for IFNAR2 in regulation of the host damage response to Af and suggests that the type of 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 or controlling pulmonary tissue damage.

Interferon receptor 2 (IFNAR2) regulates the host damage response during aspergillus pulmonary infection

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.