TY - JOUR TI - Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells AU - Mahamed, Deeqa AU - Boulle, Mikael AU - Ganga, Yashica AU - Mc Arthur, Chanelle AU - Skroch, Steven AU - Oom, Lance AU - Catinas, Oana AU - Pillay, Kelly AU - Naicker, Myshnee AU - Rampersad, Sanisha AU - Mathonsi, Colisile AU - Hunter, Jessica AU - Wong, Emily B AU - Suleman, Moosa AU - Sreejit, Gopalkrishna AU - Pym, Alexander S AU - Lustig, Gila AU - Sigal, Alex A2 - Schlesinger, Larry VL - 6 PY - 2017 DA - 2017/01/28 SP - e22028 C1 - eLife 2017;6:e22028 DO - 10.7554/eLife.22028 UR - https://doi.org/10.7554/eLife.22028 AB - 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. KW - Mycobacterium tuberculosis KW - human macrophages KW - live cell imaging KW - infection dynamics KW - necrosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -