Uptake-independent killing of macrophages by extracellular Mycobacterium tuberculosis aggregates

被引:14
作者
Toniolo, Chiara [1 ]
Dhar, Neeraj [1 ,2 ,3 ]
McKinney, John D. [1 ]
机构
[1] Swiss Fed Inst Technol Lausanne EPFL, Sch Life Sci, Lausanne, Switzerland
[2] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada
[3] Univ Saskatchewan, Dept Biochem Microbiol & Immunol, Saskatoon, SK, Canada
基金
瑞士国家科学基金会; 加拿大创新基金会;
关键词
calcium flux; EspB; plasma membrane damage; pyroptosis; time-lapse fluorescence microscopy; ESX-1 SECRETION SYSTEM; CELL-DEATH; ESAT-6; REPLICATION; APOPTOSIS; NECROSIS; CFP-10; LUNG; DISSEMINATION; PATHOGENESIS;
D O I
10.15252/embj.2023113490
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mycobacterium tuberculosis (Mtb) infection is initiated by inhalation of bacteria into lung alveoli, where they are phagocytosed by resident macrophages. Intracellular Mtb replication induces the death of the infected macrophages and the release of bacterial aggregates. Here, we show that these aggregates can evade phagocytosis by killing macrophages in a contact-dependent but uptake-independent manner. We use time-lapse fluorescence microscopy to show that contact with extracellular Mtb aggregates triggers macrophage plasma membrane perturbation, cytosolic calcium accumulation, and pyroptotic cell death. These effects depend on the Mtb ESX-1 secretion system, however, this system alone cannot induce calcium accumulation and macrophage death in the absence of the Mtb surface-exposed lipid phthiocerol dimycocerosate. Unexpectedly, we found that blocking ESX-1-mediated secretion of the EsxA/EsxB virulence factors does not eliminate the uptake-independent killing of macrophages and that the 50-kDa isoform of the ESX-1-secreted protein EspB can mediate killing in the absence of EsxA/EsxB secretion. Treatment with an ESX-1 inhibitor reduces uptake-independent killing of macrophages by Mtb aggregates, suggesting that novel therapies targeting this anti-phagocytic mechanism could prevent the propagation of extracellular bacteria within the lung.
引用
收藏
页数:20
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