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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1037-1041
Number of pages5
JournalScience
Volume357
Issue number6355
DOIs
StatePublished - 8 Sep 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank E. Pamer, M. Li, S. Kasahara, B. Zhai, and L. Heung for discussions and critical reading of the manuscript; the Memorial Sloan Kettering Cancer Center Cytology Facility, C. Franqui, and I. Leiner for technical assistance; S. Knoblaugh (Ohio State University) for histopathology; and D. Askew (University of Cincinnati) for expertise on fungal strains. This research was supported by NIH grants RO1 AI093808 (T.M.H.), R21 AI105617 (T.M.H.), RO1 AI081838 (R.A.C.), T32 GM008704 (S.R.B.), P30 CA008748 (to MSKCC), and P30GM106394 (B. Stanton, principal investigator; R.A.C., Pilot Project); Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Awards (T.M.H. and R.A.C.); Israel Science Foundation grant 835/13 (A.S.); and Deutsche Forschungsgemeinschaft grant BR1502/11-2 (G.H.B.). All data and code to understand and address the conclusions of this research are available in the main text and supplementary materials.

Fingerprint

Dive into the research topics of 'Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death'. Together they form a unique fingerprint.

Cite this