Dectin-1/CARD9-induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti-Aspergillusactivity in the lung

Abstract

ABSTRACTMyeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity toAspergillus fumigatus, the most common etiologic agent of mold pneumonia worldwide. Following engulfment ofA. fumigatusconidia, fusion of the phagosome with the lysosome, is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti-Aspergillusimmunity during infection. We found that lung neutrophils express TFEB and TFE3, and their target genes were upregulated duringA. fumigatuslung infection. Additionally,A. fumigatusinfection induced nuclear accumulation of TFEB and TFE3 in macrophages in a process regulated by Dectin-1 and CARD9 signaling. Genetic deletion ofTfebandTfe3impaired macrophage killing ofA. fumigatusconidia. However, in a murine immune competentAspergillusinfection model with genetic deficiency ofTfebandTfe3in hematopoietic cells, we surprisingly found that lung myeloid phagocytes had no defects in conidial phagocytosis or killing. Loss of TFEB and TFE3 did not impact murine survival or clearance ofA. fumigatusfrom the lungs. Our findings indicate that myeloid phagocytes activate TFEB and TFE3 in response toA. fumigatus, and while this pathway promotes macrophage fungicidal activityin vitro, genetic loss can be functionally compensated at the portal of infection in the lung, resulting in no measurable defect in fungal control and host survival.