Towards controlling mycobacterial infections

In his brief but elegant review1xMurray, P.J. Trends Microbiol. 1999; 7: 366–372Abstract | Full Text | Full Text PDF | PubMed | Scopus (49)See all References1, Murray raises a number of pertinent questions about why certain individuals are unable to sterilize lesions after exposure to Mycobacterium tuberculosis and are thus destined to remain in a state of chronic (perhaps latent) disease, which could eventually reactivate.Using a variety of approaches, the latest of which is gene-disrupted mice, those of us studying the mouse model of tuberculosis have implicated a variety of T cell subsets and the molecules they secrete or respond to as being involved in the complex process underlying acquired specific resistance to M. tuberculosis2xOrme, I.M. and Cooper, A.M. Immunol. Today. 1999; 20: 307–312Abstract | Full Text | Full Text PDF | PubMed | Scopus (191)See all References2. In his article, Murray provides an intricate description of how he views the regulation of the interferon γ (IFN-γ) signaling pathway, including the provocative suggestion that this pathway evolved specifically to combat intracellular pathogens. He also describes downregulation of the pathway by cytokines such as interleukin 10 (IL-10) and transforming growth factor β (TGF-β).One important resistance mechanism is the generation of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). NO has direct antimicrobial effects against certain laboratory strains of M. tuberculosis, but is less effective against others3xChan, J. et al. Infect. Immun. 1995; 63: 736–740PubMedSee all References, 4xRhoades, E.R. and Orme, I.M. Infect. Immun. 1997; 65: 1189–1195PubMedSee all References. This is only part of the story, however, as there is increasing evidence for a regulatory, anti-inflammatory role for iNOS that seems to affect lesion (granuloma) development directly5xGomes, M.S. et al. J. Immunol. 1999; 162: 6734–6739PubMedSee all References5.In the mouse model, the development of an initially stable granuloma correlates with the onset of chronic disease in the lungs after aerosol exposure6xRhoades, E.R., Frank, A.A., and Orme, I.M. Tuber. Lung Dis. 1997; 78: 57–66PubMed | Scopus (194)See all References6. This process is very poorly understood. In agreement with Murray, we believe that tumor necrosis factor α (TNF-α) is a key player, and we have suggested elsewhere that T cells bearing the γδ TCR might also have a regulatory role7xD’Souza, C.D. et al. J. Immunol. 1997; 158: 1217–1221PubMedSee all References7. Other cells are almost certainly involved, including CD8+ T cells. In our hands, CD8 gene knockout mice show an increased bacterial load during the chronic phase of infection, indicating they are important at this stage, rather than during the initial phase of protective immunity (I.M. Orme, unpublished). However, exactly what they are doing is less clear; where I would disagree with Murray is his statement that bacteria and their products are in and around the granuloma. In fact, only a few macrophages in the granuloma actually harbor bacilli, the remainder form a ‘wall’ of epithelioid macrophages. Granulysin might indeed damage bacteria in a test tube, but how is this molecule delivered to the site in vivo? To me, the great mystery is if only a few macrophages are actively infected, why is there such persistent, continually developing immunopathology that eventually fatally damages the lung?Despite this, there is a considerable school of thought which maintains that viable bacteria in chronically infected mice are in a state of latency. Personally, I think not. We have observed that bacteria harvested from the lungs of such mice grow at an identical rate to cultured ‘fresh’ bacilli (one would expect a lag time if the bacilli had to ‘wake up’) (A.M. Cooper and I.M. Orme, unpublished). Other evidence includes the dynamic lung pathology and the fact that isoniazid therapy reduces the bacterial load in chronically infected mice, thus indicating that cell wall mycolic acid biosynthesis is continuing. As a result, Murray’s concept of a ‘slow and cyclical’ event is most attractive.