title: Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.
abstract: Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant. In the absence of TNF, intracellular bacterial growth and granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and granuloma breakdown. Thus, TNF is not required for tuberculous granuloma formation, but maintains granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis.
authors.affiliation: Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Clay
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Volkman
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002465:Cell Movement; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004625:Embryo, Nonmammalian; D006099:Granuloma / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*; D015027:Zebrafish / Q000276:immunology / Q000382:microbiology
chemical_list: D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D048069:Tumor Necrosis Factors