Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death.
Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death.
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DOI：
10.1126/science.aan0365
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Hohl TM
中科院分区：
文献类型：
--
作者：
Shlezinger N;Irmer H;Dhingra S;Beattie SR;Cramer RA;Braus GH;Sharon A;Hohl TM
人类每天吸入霉菌分生孢子，通常会终生无症状清除。尽管骨髓细胞介导的免疫监视机制仍不清楚，但骨髓功能缺陷的个体可能会发生分生孢子萌发为组织侵入性菌丝。通过监测体内真菌生理学，我们证明肺中性粒细胞在最常见的人类霉菌病原体烟曲霉分生孢子中触发具有细胞凋亡样特征的程序性细胞死亡。抗凋亡蛋白 AfBIR1 通过抑制小鼠肺部的真菌 caspase 激活和 DNA 片段化来对抗这一过程。遗传和药理学研究表明，AfBIR1 的表达和活性是分生孢子对 NADPH（烟酰胺腺嘌呤二核苷酸磷酸还原型）氧化酶依赖性杀伤的易感性的基础，进而导致宿主对侵袭性曲霉病的易感性。免疫监视利用类似真菌凋亡的程序性细胞死亡途径来维持肺部的灭菌免疫力。
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.
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