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Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death.
Title | Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Clay, H, Volkman, HE, Ramakrishnan, L |
Journal | Immunity |
Volume | 29 |
Issue | 2 |
Pagination | 283-94 |
Date Published | 2008 Aug 15 |
ISSN | 1097-4180 |
Keywords | Animals, Apoptosis, Cell Death, Cell Movement, Cytokines, Embryo, Nonmammalian, Granuloma, Immunity, Innate, Macrophages, Mycobacterium Infections, Nontuberculous, Mycobacterium marinum, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Tumor Necrosis Factors, Zebrafish |
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. |
DOI | 10.1016/j.immuni.2008.06.011 |
Alternate Journal | Immunity |
PubMed ID | 18691913 |
PubMed Central ID | PMC3136176 |
Grant List | R01 AI036396 / AI / NIAID NIH HHS / United States R01 AI036396-19 / AI / NIAID NIH HHS / United States R01 AI054503-09 / AI / NIAID NIH HHS / United States R01 AI54503 / AI / NIAID NIH HHS / United States T32 GM07270 / GM / NIGMS NIH HHS / United States |