The role of Toll-like receptors in combating mycobacteria
Section snippets
Mycobacteria and their ligands
Although mycobacteria have evolved mechanisms of evading host defense mechanisms, they express pathogen associated molecular patterns (PAMPs), such as lipoproteins and lipoglycans that are recognized by cells of the innate immune system through the family of TLRs.
Upon fractionation of M. tuberculosis (M. tb), it was found that the major immuno-stimulatory component corresponded to a 19-kDa lipoprotein [2]. Brightbill et al. [2] demonstrated that the 19-kDa lipoprotein triggered cells to
Mycobacteria and mice: TLR2 or TLR4?
While TLR2 appears to be the major mediator of M. tb-induced cellular activation, a TLR4-activating component that appears to be heat-labile and cell-associated has also been described [3]. Studies of infection models using TLR gene disrupted mice have provided conflicting data. Initially, TLR4 was found to be required to control chronic M. tb infections. While early measurements of inflammation in the lung were similar between wild-type and C3H/HeJ mice, chronic inflammation marked by large
TLR activation by mycobacteria
TLRs mediate cellular activation by components of mycobacteria and cooperate with other branches of the innate immune system to effectively destroy mycobacteria. Two critical effector functions of the innate immune system are phagocytosis and the activation of direct anti-microbial pathways.
One of the initial responses by cells of the innate immune system upon infection with mycobacteria is to undergo phagocytosis, which is facilitated by the mannose receptor, DC-SIGN, and complement receptors.
Modulation of adaptive immune response
While dendritic cells do not display effective anti-microbial activity, their secretion of cytokines and expression of co-stimulatory molecules help modulate ensuing adaptive immune responses, supporting a Th1 biased T-cell response. Therefore, the expression of TLRs on dendritic cells helps bridge the innate and adaptive arms of the immune response. Indeed, monocyte-derived dendritic cells (DC1) have been shown to express mRNA for TLR1–6 [25], [26].
Cytokine secretion by dendritic cells is
Immune evasion
Throughout their evolution, mycobacteria have devised methods of evading the host immune response such as preventing the maturation of phagosomes. Studies are now indicating that some of its evasion techniques may involve modulating TLR activation (Fig. 1).
To begin with, it was shown that stimulation of antigen presenting cells with the M. tb 19-kDa lipoprotein results in a decrease in MHCII expression with a concomitant decrease in T-cell activation [40]. In a follow up study, the 19-kDa
TLR expression and disease
TLRs are expressed on various cells and tissue types including monocytes, macrophages, dendritic cells and epithelial cells. Given that the lung commonly encounters pathogens such as M. tb, it is critical for the lung to properly survey the surrounding area with PRRs. Indeed, analysis of human tissue reveals that the lung is a major site of TLR mRNA expression (TLRs 1–9) [47]. More specifically, TLR2 expression is found in healthy lung specimens, primarily on alveolar macrophages and alveolar
TLR polymorphisms and function
With the completion of the human genome project scientists are now able to investigate disease epidemiology by studying single nucleotide polymorphisms (SNP). To date, nucleotide polymorphisms have been identified in human TLR2 and TLR4. The polymorphism in TLR4 has been shown to abrogate responsiveness toward LPS [61]. Later, an arginine-glutamine (Arg753Gln) polymorphism in TLR2 was been identified correlated with septic shock resulting from staphylococcal infection [62]. More recently, a
Conclusions
Mammalian TLRs play a critical role in the battle against foreign pathogens such as species of Mycobacteria. In response to infection with mycobacteria, expression of TLRs help (1) initiate rapid defense mechanisms such as phagocytosis and activation of antimicrobial activity and (2) modulate ensuing adaptive immune responses in accordance with the type of infection. However, TLRs may also be targeted by mycobacteria in their attempt to evade host defense mechanisms. Finally, studies of both
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