Reactivation of latent tuberculosis infection in TNF-deficient mice.
TNF-deficient mice are highly susceptible to Mycobacterium tuberculosis H37Rv infection. Here we asked whether TNF is required for postinfectious immunity in aerosol-infected mice. Chemotherapy for 4 wk commencing 2 wk postinfection reduced CFU to undetectable levels. While wild-type mice had a slight rise in CFU, but controlled infection upon cessation of chemotherapy, TNF-deficient mice developed reactivation of infection with high bacterial loads in lungs, spleen, and liver, which was fatal within 13-18 wk. The increased susceptibility of TNF-deficient mice was accompanied by diminished recruitment and activation of T cells and macrophages into the lung, with defective granuloma formation and reduced inducible NO synthase expression. Reduced chemokine production in the lung might explain suboptimal recruitment and activation of T cells and uncontrolled infection. Therefore, despite a massive reduction of the mycobacterial load by chemotherapy, TNF-deficient mice were unable to compensate and mount a protective immune response. In conclusion, endogenous TNF is critical to maintain latent tuberculosis infection, and in its absence no specific immunity is generated.
Botha
Tania
T
Department of Health Sciences, Faculty of Applied Sciences, Cape Technikon, Cape Town, South Africa.
Ryffel
Bernhard
B
D000818:Animals; D002464:Cell Migration Inhibition; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology; D007538:Isoniazid / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics; D016131:Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D009336:Necrosis; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012008:Recurrence; D012293:Rifampin / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha; D007538:Isoniazid; D012293:Rifampin