The commonest infection route for tuberculosis is inhalation of a very small number of droplet nuclei containing virulent tubercle bacilli6. Documentation of the failure of some chronically exposed individuals (e.g. household contacts of a TB patient) to develop an infection indicates that the inhaled organisms may be inactivated before an immune response (i.e. conversion of the PPD skin test) is induced7. In most exposed individuals who are otherwise healthy, however, an infection does develop. The immune response controls the replication of the bacilli and the individuals remain disease-free until some immunosuppressive event later in life (e.g. HIV infection, immunosuppressive drug therapy, advanced age) induces endogenous reactivation TB8. This chronic infection is referred to as “latency” or “persistence” and is estimated to affect one-third of the world’s population9.
The conditions under which M.tuberculosis remains alive in the tissues for decades, and the factors which trigger its reactivation, remain unsolved mysteries10, 11. Much has been learned, however, about the mechanisms by which mycobacteria subvert the antimicrobial functions of macrophages and persist in the face of adverse conditions in the host12, 13. Recent attempts to study the gene expression profiles of mycobacteria exposed to adverse conditions, either in vitro or in vitro, and signature-tagged mutagenesis approaches to identifying mycobacterial genes necessary for persistence in experimental animal models, are beginning to shed some light on these important questions14, 15. Pulmonary TB may also develop following exogenous re-infection in a previously infected person16. The relative contributions of primary TB, endogenous reactivation TB, and exogenous re-infection TB to the spectrum of disease appear to vary widely in different geographical settings.
In primary pulmonary TB, the inhaled mycobacteria likely encounter the alveolar macrophage as their initial host target cell2. Direct infection of alveolar (Type II) epithelial cells may also occur, however, the contribution of epithelial cells to the initial host- pathogen interaction is not clear17. Mycobacterial constituents are known to serve as ligands for the binding and internalisation of tubercle bacilli, and for various pathogen-recognition receptors (e.g. Toll-like receptors) on macrophages, leading to the activation of those cells
and the production of pro-inflammatory cytokines (e.g. TNF-α) and chemokines18-21. The roles of various adhesion proteins, chemokines, and chemokine receptors in the trafficking of immune cells into infectious foci are topics of intense investigation22. Other cells of the innate host defense system, such as natural killer (NK) cells, may also play a role in promoting activation of alveolar and blood-borne monocyte-macrophages in this early phase of the infection23. During the ensuing inflammatory response and following initial replication in the alveolar macrophages, mycobacteria are taken in the draining lymph to the regional lymph nodes, where they replicate further. It is in the lymph nodes where mycobacterial antigens are first presented to naive CD4+ and CD8+ T-cells, likely by infected dendritic cells which are capable of stimulating a CD4+ Th1 effector cell response24, 25. After a short period of replication in the pulmonary lymph nodes, viable mycobacteria leave the nodes in the efferent lymph, enter the blood stream via the thoracic duct, and appear in the spleen and other organs26. Concomitant with extra-pulmonary dissemination, which apparently occurs in all infected individuals, the host begins to express evidence of a CD4+ T-cell-mediated immune response (e.g. PPD skin test conversion). Eventually, viable bacilli make their way back to the lung in the bloodstream where they infect all lung lobes uniformly in a process known as “haematogenous re-seeding”27. Thus, the lung of every infected individual receives two inocula of mycobacteria; the initial implantation from the airway, and a second shower of bacilli from the blood. The blood-borne organisms establish so-called “secondary” granulomas, in which the organisms persist in the face of a very active immune response28. It is one of these secondary granulomas which are thought to be the “reactivatable site” in post-primary TB29.
Following the induction and expansion of CD4+ Th1 effector cell populations in the pulmonary lymph nodes, these effector cells leave the nodes and home to the inflamed sites of active infection in the lungs and other tissues. There, the Th1 cells are activated to produce their signature cytokines, including IFNα30. The combination of IFNα from the Th1 cells and TNF-α from activated phagocytes likely act synergistically to activate macrophages to inhibit the growth of the mycobacteria1, 32.While TNF-α is apparently essential for resistance to TB30, it is also responsible for local tissue destruction, central necrosis of the granuloma, and impairment of Type 1 T-cell immunity34. Successful modulation of the intense inflammatory response in the granulomas by anti-inflammatory cytokines such as TGF-α, and IL-10 allows the host to control mycobacterial replication without compromising lung function. These cytokines are, however, also known to suppress Type 1 immunity35. Apparently, CD8+ T-cells may also play a role in resistance to TB, by producing macrophage-activating cytokines and differentiating into effector cytolytic T-cells (CTL), although their precise contributions are unclear36.
The anti-mycobacterial mechanisms expressed by activated macrophages, including the identification of essential effector molecules, remain to be elucidated. The ability
of the activated macrophage to overcome the pathogen-induced block of endosome maturation and phagosome-lysosome fusion is undoubtedly important37, 38.Induction of the receptor (VDR) for the vitamin D metabolite, 25-hydroxycholcalciferol (25-HCC), as well as the hydroxylase which then forms 1,25-dihydroxycholecalciferol (1,15-DHCC), appears to be part of the mechanism which help the cells to destroy the intracellular pathogen, combined as it is with the generation of the antibiotic peptide, cathelicidin (see Chapter 4, Vitamin D). Reactive oxygen intermediates (e.g. hydroxyl radical, singlet oxygen, hydrogen peroxide, etc) are also involved, while the role of nitric oxide (NO) is much less clear in humans than in murine models of TB39, 40.
Co-infection with HIV changes the above scenario dramatically. While there is little evidence that HIV infection predisposes an individual to increased risk of primary infection, it clearly increases the risk of progression from infection to disease by orders of magnitude41.This is likely due to the adverse effects of HIV on the CD4+ T-cells which are essential for control of mycobacterial growth, as well as defects in macrophage and other cell functions which are known to accompany HIV infection.