Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages.
Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages.
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DOI：
10.1111/cmi.12485
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发表时间：
2016-01
影响因子：
3.4
通讯作者：
Dockrell DH
中科院分区：
文献类型：
--
作者：
Jubrail J;Morris P;Bewley MA;Stoneham S;Johnston SA;Foster SJ;Peden AA;Read RC;Marriott HM;Dockrell DH
巨噬细胞是组织中对细菌的早期先天反应的关键效应器。吞噬作用和杀死细菌是细菌清除所必需的相互关联的功能，但当巨噬细胞受到大量主要医学病原体金黄色葡萄球菌的挑战时，限速步骤尚不清楚。我们发现，当暴露于金黄色葡萄球菌（Newman、SH1000 和 USA300 菌株）的大接种物时，巨噬细胞的细胞内杀伤能力有限，并且无法将持续的吞噬作用与持续的微生物杀伤相匹配。巨噬细胞摄入金黄色葡萄球菌与吞噬后细菌活力迅速下降有关。然而，并非所有细菌都在吞噬溶酶体中被杀死，我们证明吞噬溶酶体的酸化减少，这与吞噬溶酶体成熟失败和组织蛋白酶 D 活化减少有关。这导致巨噬细胞中活细胞内细菌的积累。我们发现巨噬细胞无法参与细胞凋亡相关的细菌杀伤。 Ultittop 与活细菌配对的巨噬细胞进行细胞裂解，活细菌被释放并可以被其他巨噬细胞内化。我们发现，当杀灭被淹没时，裂解和再摄取的循环会随着时间的推移维持活细胞内细菌池，并在小鼠模型中证明肺泡巨噬细胞的细胞内持久性。
Macrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate‐limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis‐associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model.