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Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells

2017; eLife Sciences Publications Ltd; Volume: 6; Linguagem: Inglês

10.7554/elife.22028

2050-084X

Deeqa Mahamed, Mikaël Boullé, Yashica Ganga, Chanelle Mc Arthur, Steven Skroch, Oom Lance, Oana Catinas, Kelly Pillay, Myshnee Naicker, Sanisha Rampersad, Colisile Mathonsi, Jessica Hunter, Emily Wong, Moosa Suleman, Gopalkrishna Sreejit, Alexander S. Pym, Gila Lustig, Alex Sigal,

Infectious Diseases and Tuberculosis

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.