Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death

Neta Shlezinger shlezinn@mskcc.org ¹ Henriette Irmer ² Sourabh Dhingra ³ Sarah R. Beattie ³ Robert A. Cramer ³ Gerhard H. Braus ² Amir Sharon ⁴ Tobias M. Hohl ¹

¹Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
²Department of Molecular Microbiology and Genetics, University of Göttingen, Göttingen, Germany
³Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth, New Hampshire, USA
⁴Department of Molecular Biology and Ecology of Plants, Tel Aviv University, Tel Aviv, Israel

Humans inhale mold conidia daily and typically experience lifelong asymptomatic clearance. Conidial germination into tissue-invasive hyphae can occur in individuals with defects in myeloid function, though the mechanism of myeloid cell-mediated immune surveillance remains unclear. By monitoring fungal physiology in vivo, we demonstrate that lung neutrophils trigger programmed cell death with apoptosis-like features in Aspergillus fumigatus conidia, the most prevalent human mold pathogen. An anti-apoptotic protein, AfBIR1, opposes this process by inhibiting fungal caspase activation and DNA fragmentation in the murine lung. Genetic and pharmacologic studies indicate that AfBIR1 expression and activity underlies conidial susceptibility to NADPH oxidase-dependent killing and, in turn, host susceptibility to invasive aspergillosis. Immune surveillance exploits a fungal apoptosis-like programmed cell death pathway to maintain sterilizing immunity in the lung.