We have used a mouse model of Mycobacterium avi­um infection to dissect the immune response to mycobacterial infections looking at protective immunity mechanisms (both innate and adaptive) and immunopathology (granuloma formation, fibrosis, and necrosis, peripheral lymphopenia, and thymic atrophy). Thus we now know that protective immunity requires gamma interferon (IFNg), the interleukins 6 and 12, tumor necrosis factor (TNF), the CD30 and CD40 molecules and the TLR2 receptor. We pinpointed the pivotal role of IFNg in the mechanisms leading to granuloma formation and necrosis as well as the cell loss of central and peripheral lymphoid organs while excluding major players as the mediators of such pathology. For example, granuloma necrosis does not require the participation of apoptosis-inducing mediators such as NO, oxygen reactive species, TNF, Fas or TRAIL nor can it be prevented by Bcl-2. The deficiency in the same molecules does not affect the development of peripheral lymphopenia. Amélia Sarmento has looked at immune alterations in the physiology of monocytes from Inflammatory Bowel Disease (IBD) patients and identified differences in the production of TNF in the cells of Crohn’s disease patients. Future research goals In addition to pursuing the research described above, recent collabo­rations with extramural groups have led to the analysis of the immuno-modulatory role of mycobacterial lipoglycans (with Ben Appelmelk, Germain Puzo and Jérôme Nigou) and the role of apoptosis in M. tuberculosis control (with Otília Vieira and researchers from Harvard Medical School). Selected references Flórido et al. 2002 Immunological basis of the development of necrotic lesions following Mycobacterium avium infection. Immunology 106: 590. Gomes et al. 2004 Limited role of the Toll-like receptor (TLR)-2 in resistance to Mycobacterium avium. Immunology 111: 179. Flórido et al. 2005 Gamma interferon-induced T cell loss in virulent Mycobacterium avium infection. Infect. Immun. 73: 3577. Flórido & Appelberg. 2007 Characterization of the deregulated immune activation occurring at late stages of mycobacterial infection in Tumor Necrosis Factor-deficient mice. J. Immunol. 179: 7702. Flórido et al. 2009 Constitutive expression of Bcl-2 in the hematopoietic compartment alters the metabolism of iron and increases resistance to mycobacterial infection. Clin. Exp. Immunol 156: 61. Nóbrega et al. 2010 Dissemination of Mycobacteria to the Thymus Renders Newly Generated T Cells Tolerant to the Invading Pathogen. J. Immunol. 184: 351.

Microbiology and Immunology of Infection