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* Laboratory of Microbiology and Immunology of Infection, Instituto de Biologia Molecular e Celular, and
Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Porto, Portugal
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-
, 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- production and late up-regulation of TRAIL which may contribute to granuloma disintegration.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants POCTI/32629/99 and PSIDA/MGI/49647/2003 from the Portuguese Science and Technology Foundation (FCT; Portugal) and SDH.IC.I.01.15 from the Calouste Gulbenkian Foundation (Portugal). M. F. received a fellowship from the FCT.
2 Address correspondence and reprint requests to Dr. Rui Appelberg, Laboratory of Microbiology and Immunology of Infection, Institute for Molecular and Cell Biology, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. E-mail address: rappelb{at}ibmc.up.pt
3 Abbreviations used in this paper: MST, mean survival time; BCG, bacillus Calmette-Guérin.
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