title: Intracellular growth ofMycobacterium tuberculosisafter macrophage cell death leads to serial killing of host cells.
abstract: A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrictMycobacterium 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.
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Deeqa
authors.initials: D
authors.lastname: Mahamed
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Mikael
authors.initials: M
authors.lastname: Boulle
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Yashica
authors.initials: Y
authors.lastname: Ganga
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Chanelle
authors.initials: C
authors.lastname: Mc Arthur
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Steven
authors.initials: S
authors.lastname: Skroch
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Lance
authors.initials: L
authors.lastname: Oom
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Oana
authors.initials: O
authors.lastname: Catinas
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Pillay
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Myshnee
authors.initials: M
authors.lastname: Naicker
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Sanisha
authors.initials: S
authors.lastname: Rampersad
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Colisile
authors.initials: C
authors.lastname: Mathonsi
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hunter
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|Division of Infectious Diseases, Massachusetts General Hospital, Boston, United States.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Wong
authors.affiliation: Department of Pulmonology and Critical Care, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Department of Pulmonology, Inkosi Albert Luthuli Central Hospital, Durban, South Africa.
authors.forename: Moosa
authors.initials: M
authors.lastname: Suleman
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Gopalkrishna
authors.initials: G
authors.lastname: Sreejit
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Pym
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.
authors.forename: Gila
authors.initials: G
authors.lastname: Lustig
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV, Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Alex
authors.identifier: http://orcid.org/0000-0001-8571-2004
authors.initials: A
authors.lastname: Sigal
mesh_terms: D016923:Cell Death; D002478:Cells, Cultured; D004705:Endocytosis; D006801:Humans; D000069416:Intravital Microscopy; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000254:growth & development*
keywords: Mycobacterium tuberculosis; computational biology; human; human macrophages; infection dynamics; infectious disease; live cell imaging; microbiology; necrosis; systems biology