Elsevier

Seminars in Immunology

Volume 16, Issue 1, February 2004, Pages 35-41
Seminars in Immunology

The role of Toll-like receptors in combating mycobacteria

https://doi.org/10.1016/j.smim.2003.10.005Get rights and content

Abstract

In the battle against infections with mycobacteria, the body employs components of both the innate and adaptive arms of the immune system. Toll-like receptors (TLRs) mediate the activation of cells of the innate immune system leading to dynamic functions including direct anti-microbial activity, induction of cytokine secretion, triggering dendritic cell maturation, and triggering apoptosis. Furthermore, TLR activation is capable of modulating the adaptive immune response with a bias towards a Th1 T-cell response. However, the activation of TLRs by mycobacteria may also provide a means of immune evasion. Therefore, the modulation of TLR activation can influence the ability to properly destroy invading pathogens such as 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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