Project Summary

The rise in the use of immunosuppressive therapies to treat human diseases has led to an increase in pulmonary fungal infections, caused by the filamentous fungus Aspergillus fumigatus (Af), that has a global incidence of over 300,000 cases/year with a high mortality rate (40-80%). An important contributor to Af infection outcome, is the level of tissue/organ damage the host incurs. Damage can result from infection and/or the host response to infection and can contribute to creating transiently impaired/suppressed immune environments. As an opportunistic human pathogen, Af thrives in the lungs of individuals with impaired immune responses. The recent cases of influenza-infected patients acquiring aspergillosis, suggest that anti-influenza immune responses create transiently suppressed lung immune environments that enable Af infection. Influenza’s manipulation of type I interferon (IFN) signaling is known to make lungs permissive to bacterial infection, suggesting that type I IFN signaling may regulate lung immune environments.

This project seeks to further understand the contribution of signaling via the individual subunits of the type I IFN receptor (IFNAR), IFNAR1 and IFNAR2, in controlling damage responses and clearance of Af during infection. Preliminary data from the first year of this grant demonstrate that absence of IFNAR2 (Ifnar2-/- mice) results in increased damage (from immune and non-immune compartments), inflammation, and morbidity in response to Af infection, and absence of IFNAR1 (Ifnar1-/- mice) did not. Additionally, presence of IFNAR2 in WT or Ifnar1-/- mice resulted in early decreased Af conidia clearance compared to Ifnar2-/- mice, but no difference in conidia killing by macrophages or neutrophils ex vivo, suggesting that IFNAR2 interferes with IFNAR1-mediated Af conidia clearance and that this requires cell-cell interactions/signaling in vivo. Based on these preliminary results, in this renewal, to address our hypothesis that IFNAR2, while it regulates the host damage response, also interferes with the ability of IFNAR1 to control Af infection, we will use a bone-marrow (BM) chimera approach to identify the cellular compartment involved in and contributing to IFNAR2 regulation of host damage and anti-fungal immunity. 

The results from this proposal will begin to elucidate how type I IFN signaling from different cellular compartments differentially regulate the host damage response during Af infection and its role in anti-fungal immunity. Thus, these results will allow for better understanding of the protective mechanisms of type I IFN signaling, which could guide the design of new immune therapies for Af in the future.

Project Aims

  1. To identify the effector cells and their contribution to IFNAR2-regulated damage responses and Af clearance. Our preliminary data from the first year of this grant suggest that epithelial/endothelial and myeloid innate effector cells both have roles in IFNAR2 regulation of damage and anti-fungal immunity during Af lung infection. Using a BM chimera approach, in this renewal we will identify the cellular compartment involved in and contributing to IFNAR2’s regulation of host damage and anti-fungal immunity. We will employ WT/Ifnar2-/- BM-chimeric mice to reveal whether IFNAR2 expression on BM-derived and/or non-BM-derived cells is required for the IFNAR2-medaited damage response. Utilizing Ifnar1-/-/Ifnar2-/- BM chimeric mice we will determine whether absence of IFNAR2 expression on either BM-derived cells or non-BM-derived cells is required for improved Af clearance, which we found to be IFNAR1 dependent; and how cellular expression of IFNAR2 affects IFNAR1-regulated fungal clearance. These experiments will allow us to determine the individual contribution of IFNAR1 and IFNAR2-signaling to anti-fungal host immunity and regulation of the host pulmonary damage response.