Dissecting the Role of Type I Interferon as Regulator of Innate Antifungal Immunity 2227148

Abstract

Abstract Introduction Aspergillus fumigatus (Af) is the main cause of invasive pulmonary aspergillosis (IA), responsible for over 90% of cases, and has been identified by the World Health Organization (WHO) as the only mold among its list of critical fungal pathogens.Myeloid cells, CCR2+ inflammatory monocytes (CCR2+Mo), and neutrophils are necessary to control pulmonary Af infection.CCR2+Mo gives rise to monocyte-derived dendritic cells (mo-DCs) and alveolar macrophages (AMs), key effector populations within the CD11c+ cell compartment.Our lab found that mice with defective expression of the type I interferon receptor (IFNAR1) had increased mortality and fungal burden.Furthermore, mice with a deficiency in STAT1, a key transcription factor activated by IFNs, on CCR2+Mo and CD11c+cells had increased mortality, reduced ROS formation, and diminished control of fungal burden.Therefore, we hypothesize that type I IFNs regulate antifungal immunity through CCR2+Mo and CD11c+cells, enhancing host defense against Af infections. Methods Using CCR2creIFNAR1fl/fl and CD11ccreIFNAR1fl/fl mice, we evaluated the immune cell recruitment in bronchoalveolar lavage fluid and lung tissue.Antifungal responses were examined by ROS production and visualization of conidia-killing using the Af-FLARE strain.Furthermore, monocytes were sorted and analyzed for bioenergetic function using the Seahorse Analyzer and fungal burden by colony-forming units. Results Mice deficient in type I IFNs in CCR2+Mo and CD11c+cells succumbed to IA with impaired ROS production and increased fungal burden.Af viability was significantly increased in CCR2creIFNAR1fl/fl mice, indicating decreased fungal clearance.The seahorse analysis demonstrated decreased oxygen consumption rate, spare respiratory capacity, and extracellular acidification rate in monocytes from CCR2creIFNAR1fl/fl. Conclusion These findings can reveal new immunological mechanisms to enhance host defense against Af and could also help improve outcomes in patients at risk for aspergillosis. Funding Source n/a Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)