Report

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

See allHide authors and affiliations

Science  08 Sep 2017:
Vol. 357, Issue 6355, pp. 1037-1041
DOI: 10.1126/science.aan0365

You are currently viewing the abstract.

View Full Text

Survivin' neutrophil surveillance

Humans constantly inhale fungal spores. Why don't we suffer more invasive infections from ubiquitous fungal molds such as Aspergillus fumigatus? Working in mice, Shlezinger et al. found that neutrophils phagocytosed germinating fungal spores deep in the lungs (see the Perspective by Wiesner and Klein). Once engulfed, the fungal cells underwent programmed cell death, likely induced by phagocyte NADPH oxidase. Fungal strains engineered to overexpress a fungal survivin homolog resisted cell death by inhibiting caspase-3 and -7. When a Survivin antagonist was applied, more fungal cells died. These findings may lead to therapies for immunocompromised patients threatened by invasive fungal lung infections.

Science, this issue p. 1037; see also p. 973

Abstract

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.

View Full Text