1.4.1 Host infection by mycobacteria
Current estimates provided by the World Health Organisation (WHO) suggest that approximately one third of the world’s population is infected with Mycobacterium tuberculosis, although fortunately, this does not lead to active disease in the majority of individuals (Flynn & Chan, 2001a). The immune response of the host that is mounted against infection by M. tuberculosis is generally successful in containing the bacilli within granulomatous lesions (Raupach & Kaufmann, 2001), although often not eliminating the pathogen completely. In a small number of cases acute active tuberculosis can result, probably due to the lack of initiation of an appropriate immune response (Manca et a l, 2001). However, in most cases of M. tuberculosis infection, the individual remains asymptomatic and non- infectious, and this clinical latency often extends for the lifetime of the individual (Parrish et a l, 1998), and may provide the host with immunity against reinfection (Collins, 1998). Reactivation of the endogenously persisting infection and the onset of active disease are required for the bacilli to successfully spread to a new host. In approximately 10% of infected individuals (Flynn & Ernst, 2000), reactivation of the latent infection occurs, usually in response to perturbations of the immune response and active tuberculosis ensues. In many cases of active
tuberculosis an obvious immunodeficiency is not found, however, infection with human immunodeficiency virus (HIV), treatment with corticosteroids, ageing, and alcohol or drug abuse increase the potential for reactivation of latent tuberculosis (Flynn & Chan, 2001b).
Mycobacterium tuberculosis has developed a number of successful mechanisms for evading elimination by a strong, cell-mediated host immune response (Ulrichs & Kaufmann, 2002). Therefore, a more complete understanding of the roles each component of the immune system plays in protection or exacerbation of tuberculosis, as well as of the bacterium’s weapons to evade those components will enhance development of preventive and therapeutic strategies against this enormously successful pathogen.
1.4.2 Macrophage infection by Mycobacterium tuberculosis
Mycobacterium tuberculosis is usually acquired by the inhalation of small numbers of the aerosolised bacterium. Once inhaled, most of the M. tuberculosis
organisms will settle in the upper respiratory epithelium where they are most likely to be expelled from the host by the mucociliary escalator (Fenton & Vermeulen, 1996). However, a small number of the bacteria (approximately 10%) will reach the respiratory bronchioles and alveoli of the deep lung, where they are phagocytosed by alveolar macrophages and are either killed, or else survive as intracellular pathogens to initiate an infection (Dannenberg, 1993). In a minority of individuals, the immune response to M. tuberculosis is suboptimal. This allows the organism to multiply to large numbers, kill their host macrophages, and spread to other organs and into the blood, leading to primary active disease, a condition
characterised by persistent fatigue, anorexia, progressive weight loss, low-grade fever, production of a chronic, often contagious cough and death (Zahrt & Deretic, 2002). However, in the majority of immunocompetent individuals, macrophages become activated following the emergence of a productive TrI-type-cell-mediated immune response, initiating a broad spectrum of host defences against the bacterium, and are proficient in killing the bacilli (Russell, 1995). Therefore, most cases actually resolve without clinical tuberculosis. More commonly, the host’s immune response serves to contain the infection rather that eliminating the infection entirely. The organisms may persist in low numbers inside a granulomatous containment in a poorly understood dormant or quiescent state termed latency (Murray, 1999), from which they may emerge at a later date when host conditions are more favourable, such as suppression of the host’s immune system, and this may result in active tuberculosis (Fig. 4).
1.4.3 Macrophage activation: TrI response
Mycobacterium tuberculosis and Mycobacterium leprae survive and replicate primarily within the phagosomes of macrophages (Russell, 2001). Within the macrophage they are shielded from the effects of both antibodies and cytotoxic T cells. It is thus ironic that these bacteria infect the very cells that have evolved to destroy intracellular pathogens. Such pathogens may be eliminated from the host however, when the macrophage becomes activated by a T rI cell (Mitsuyama, 1998). It is the action of these cells that leads to the red, swollen and potentially painful lesions caused by the delayed type hypersensitivity (DTK) response due to the administration of tuberculin (a mixture of peptides and carbohydrates) in the Mantoux test for tuberculosis infection used prior to a BCG vaccination. Armed
Figure 4: Infective life cycle of Mycobacterium tuberculosis. M. tuberculosis
acquired by inhalation resides and multiplies in lung macrophages. Bacteria replicate during the innate stages of immunity and reach high numbers in the macrophages of immunodeficient hosts where they cause active disease. If untreated, organisms spread to other parts of the body and can cause death of the host. Bacteria infecting immunocompetent hosts are usually controlled by cell- mediated immunity and are either eliminated or else persist in low numbers in a latent infection. Suppression of the immune system at a later date can result in reactivation of bacterial multiplication and the continuation of the infectious cycle.
Inhalation of bacteria
Bacteria reach lungs and enter resident alveolar macrophages
Bacteria multiply within macrophages
Bacteria coughed up in sputum Lesion begins to form
Bacteria stop growing Lesion calcifies
Immune supression