Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity
Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity
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DOI：
10.1016/j.chom.2015.12.002
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发表时间：
2016-01-13
影响因子：
30.3
通讯作者：
Chamilos, Georgios
中科院分区：
文献类型：
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作者：
Akoumianaki, Tonia;Kyrmizi, Irene;Chamilos, Georgios
隐藏病原体相关分子模式（PAMPs）是真菌避免免疫识别的主要策略。在萌发过程中，PAMPs的表面暴露会使病原体变得脆弱。因此，在烟曲霉萌发过程中β -葡聚糖表面暴露激活了atg5依赖性自噬途径，称为lc3相关吞噬（LAP），从而促进真菌的杀死。我们发现LAP激活还需要烟曲霉细胞壁黑色素的遗传、生化或生物（萌发）去除。在Atg5缺失的巨噬细胞和小鼠造血细胞中，当Atg5条件失活后，黑素缺失的烟曲霉毒力恢复。从机制上讲，黑曲霉通过从吞噬体中排除p22phox亚基来抑制NADPH氧化酶依赖的LAP激活。因此，在空气传播的真菌萌发过程中同时发生的两个事件，PAMPs的表面暴露和黑色素的去除，对于LAP的激活和真菌的杀死是必要的。LAP阻断是黑色素的一种普遍特性，这一发现具有广泛的生理意义。
Concealing pathogen-associated molecular patterns (PAMPs) is a principal strategy used by fungi to avoid immune recognition. Surface exposure of PAMPs during germination can leave the pathogen vulnerable. Accordingly, beta-glucan surface exposure during Aspergillus fumigatus germination activates an Atg5-dependent autophagy pathway termed LC3-associated phagocytosis (LAP), which promotes fungal killing. We found that LAP activation also requires the genetic, biochemical or biological (germination) removal of A. fumigatus cell wall melanin. The attenuated virulence of melanin-deficient A. fumigatus is restored in Atg5-deficient macrophages and in mice upon conditional inactivation of Atg5 in hematopoietic cells. Mechanistically, Aspergillus melanin inhibits NADPH oxidase-dependent activation of LAP by excluding the p22phox subunit from the phagosome. Thus, two events that occur concomitantly during germination of airborne fungi, surface exposure of PAMPs and melanin removal, are necessary for LAP activation and fungal killing. LAP blockade is a general property of melanin pigments, a finding with broad physiological implications.