Reactivation of latent tuberculosis by an inhibitor of inducible nitric oxide synthase in an aerosol murine model.
Exposure to Mycobacterium tuberculosis results in clinical tuberculosis only in a small percentage of healthy individuals. In most instances the bacilli are controlled by the immune system and survive in a latent state within granuloma. Immunosuppression, however, may result in reactivation of infection, resulting in clinical disease. Using a low-dose aerosol infection (30 colony-forming units) in mice, we describe a short-duration model for studying spontaneous and drug-induced reactivation of anti-tuberculous drug-treated, latent tuberculosis infection. Although a 4-week treatment with rifampicin and isoniazid reduced the number of bacilli to undetectable levels, the infection spontaneously reactivated following therapy. By contrast, an 8-week treatment period induced a state of latent infection, requiring immunosuppression to reactivate infection. Finally, a 12-week treatment period eliminated the bacilli completely and aminoguanidine did not induce reactivation of infection. In view of the fact that therapy in the selected protocol reduces the mycobacterial load to undetectable levels, the data suggest that an 8-week treatment period is necessary and sufficient to mount protective immunity in mice.
Botha
Tania
T
Department of Biomedical Sciences, Faculty of Applied Sciences, Cape Technikon, Cape Town, South Africa.
Ryffel
Bernhard
B
D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use; D002908:Chronic Disease; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007165:Immunosuppression Therapy; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012008:Recurrence; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine