Dissecting the role of type I IFN as regulator of innate antifungal immunity

About This Grant

PROJECT SUMMARY Fungal pathogens present a significant risk to immunocompromised individuals because they contribute to increased morbidity and mortality worldwide. Aspergillus fumigatus (Af) is the main cause of invasive pulmonary aspergillosis (IA) and has been identified by the World Health Organization as a critical fungal pathogen for further study. These findings highlight the increasing incidence of IA and the medical need for new strategies to treat invasive fungal infections, such as Af. Myeloid cells, CCR2+ inflammatory monocytes (CCR2+Mo), and neutrophils are necessary for controlling pulmonary Af infection. CCR2⁺Mo gives rise to monocyte-derived dendritic cells (mo-DCs) and alveolar macrophages (AMs), which are key effector populations within the CD11c⁺ cell compartment. In previous studies, we found that CCR2+Mo depleted mice affect neutrophil responses due to a decreased ability of neutrophils to produce reactive oxygen species (ROS) and eliminate Af conidia. Furthermore, neutrophils play a critical role in regulating the antifungal response of CCR2+Mo and promote the differentiation of protective mo-DCs. In previous work to understand the mechanism of monocyte-dependent neutrophil regulation, the lab performed a systems biology approach based on differential neutrophil transcriptomics, which allowed us to identify a strong interferon signaling (IFNs) gene signature. Since STAT1 is key to IFNs, we performed survival studies and found that deleting STAT1 in CCR2+Mo succumbed to Af, impaired maturation of mo-DCs, and reduced ROS formation. Additionally, when we deleted STAT1 in CD11c+ cells, we found that it affected mortality and increased the fungal burden. This confirms that STAT1 expression on CCR2+Mo and CD11c+ cells is required for defense against Af. To assess the importance of Type I IFN, we infected mice with defective expression of the type I IFN receptor (IFNAR1), which developed IA due to their inability to control fungal growth. In a kinetic analysis of IFN-α expression following Af infection, we demonstrated a rapid induction of type I IFN with peak protein expression observed at 12 hours post-infection. Although we have previously shown that type I IFNs are essential for controlling Af, their specific contribution to antifungal immunity in CCR2⁺Mo and CD11c+ cells remains unclear. We hypothesize that type I IFNs are essential for regulating antifungal immunity through CCR2⁺Mo and CD11c+ cells by activating the IFNAR1, triggering STAT1-dependent signaling pathways that enhance defense mechanisms against infections caused by Af. Two specific aims are proposed: 1) to examine the role of type I IFNs in regulating the antifungal response of CCR2⁺Mo and 2) to elucidate the mechanisms of whether type I IFNs regulate the antifungal response of CD11c+ cells. Achieving the proposed objectives will uncover novel insights into how type I IFNs influence antifungal immune responses via CCR2⁺Mo and CD11c+ cells. These findings have the potential to reveal new immunological pathways that strengthen host defenses against Af and inform strategies to improve outcomes in individuals vulnerable to aspergillosis.