3 years ago

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

Robert A. Cramer, Sarah R. Beattie, Sourabh Dhingra, Tobias M. Hohl, Neta Shlezinger, Gerhard H. Braus, Henriette Irmer, Amir Sharon

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, although 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 antiapoptotic 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 underlie conidial susceptibility to NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) 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.

Publisher URL: http://science.sciencemag.org/cgi/content/short/357/6355/1037

DOI: 10.1126/science.aan0365

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