Role of toll-like receptors sensing and control Ofmycobacterial infection

Abstract

Microbial products including mycobacterial antigens are recognized by distinct Toll like receptors (TLR) resulting in activation of cells of the innate immune system. Several mycobacterial components such lipomannan have been identified with dual functions -activating antigen presenting cells via TLR2 and inhibiting TLR activation pathways in a TLR independent way. Ablation of TLR signalling as described for mice deficient for the common adaptor protein MyD88 revealed that TLRs are crucial for the activation of an innate immune response as MyD88 deficient mice are highly sensitive to infection with Mycobacterium tuberculosis. Despite the profound defect of the innate immune response, MyD88 deficiency allows the emergence of an adaptive immunity. These data demonstrate that activation of multiple TLRs contributes to an efficient innate response to mycobacteria, while MyD88-dependent signalling is dispensable to generate adaptive immunity. Background: Tuberculosis, immune response and Toll-Like receptors Infectious tuberculosis due to Mycobacterium tuberculosis (MTb), an intracellular pathogen capable of surviving and persisting within host mononuclear cells, represents a major global health challenge. A coordinated response of cells of the innate and adaptive immune system is required to control infection (Flynn and Chan, 2001; North and Jung, 2004). The pathogen sequestered within macrophages within granuloma, a dynamic structure containing activated lymphocytes and macrophages contains the spread of infection. Gene targeted mice and neutralising antibodies demonstrated critical mediators controlling M. tuberculosis infection, including IFNγ, IL-12, IL-23, TNF, lymphotoxins, CD40 and nitric oxide (Flynn and Chan, 2001; North and Jung, 2004). Mycobacteria have evolved to resist the eradication by macrophages by using elaborate evasion mechanisms (Flynn and Chan, 2003). In a healthy host a subclinical latent or chronic infection may persist (Gomez and McKinney, 2004). Neutralisation of IFNγ or TNF, inhibition of iNOS, or T cell depletion leads to reactivation of latent infection (Botha l, 2003). Continous macrophage and T lymphocyte activation control the viable, but sequestered bacilli within phagocytes in the granulomas structure. We hypothesise that mycobacterial products released by the sequestered bacilli, such as glycolipids PIMs, LM, LAM, lipoproteins and other mycobacterial factors,