Characterization of the deregulated immune activation occurring at late stages of mycobacterial infection in TNF-deficient mice.
In the absence of TNF, mice infected with Mycobacterium avium suffer a peculiar disintegration of the granulomas, with extensive apoptosis and necrosis of their cells, occurring during the course of the infection and leading to the death of the animals within a few days of its onset. The survival time depends on the virulence of the infecting strain as well as on the dose and route of infection. Intravenously infected mice developed the typical lesions in hepatic granulomas whereas aerosol-infected animals developed them in the lung granulomas. At the onset of the development of pulmonary granuloma disintegration, extensive expansion of T cells, with intense up-regulation of activation markers, massive exacerbation of their ability to secrete IFN-gamma, and increased cytotoxic activity of both CD4(+) and CD8(+) T cells were observed. Forced expression of Bcl2 did not prevent the early death of infected TNF-deficient mice leading merely to a modest increase in survival times. The expression of the FasL on T cells was not affected but there was an intense up-regulation of the TRAIL in T cells and, in particular, myeloid cells. We thus show that an exacerbated immune response occurs in TNF-deficient hosts during M. avium infections that leads to enhanced IFN-gamma production and late up-regulation of TRAIL which may contribute to granuloma disintegration.
Flórido
Manuela
M
Laboratory of Microbiology and Immunology of Infection, Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.
Appelberg
Rui
R
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007275:Injections, Intravenous; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D009162:Mycobacterium avium / Q000276:immunology / Q000302:isolation & purification; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000172:deficiency* / Q000276:immunology*
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D048069:Tumor Necrosis Factors; C052617:Bcl2 protein, mouse