Role of Toll-like receptors in pathogen recognition

Abstract

The innate immune system relies on a vast array of non-clonally expressed pattern recognition receptors for the detection of pathogens. Pattern recognition receptors bind conserved molecular structures shared by large groups of pathogens, termed pathogen-associated molecular patterns. The Toll-like receptors (TLRs) are a recently discovered family of pattern recognition receptors which show homology with the Drosophila Toll protein and the human interleukin-1 receptor family. Engagement of different TLRs can induce overlapping yet distinct patterns of gene expression that contribute to an inflammatory response. The TLR family is characterized by the presence of leucine-rich repeats and a Toll/interleukin-1 receptor-like domain, which mediate ligand binding and interaction with intracellular signaling proteins, respectively. Most TLR ligands identified so far are conserved microbial products which signal the presence of an infection, but evidence for some endogenous ligands that might signal other danger conditions has also been obtained. Molecular mechanisms for pathogen-associated molecular pattern recognition still remain elusive but seem to be more complicated than initially anticipated. In most cases, direct binding of microbial ligands to TLRs still has to be demonstrated. Moreover, Drosophila TLRs bind endogenous ligands, generated through a proteolytic cascade in response to an infection. In the case of endotoxin, recognition involves a complex of TLR4 and a number of other proteins. Moreover, TLR heterodimerization further extends the spectrum of ligands and modulates the response towards specific ligands. The fact that TLR expression is regulated in both a cell type- and stimulus-dependent fashion further contributes to the complexity.

FIG. 1.

Short overview of a TLR signaling cascade. TLR signaling relies on the function of the adaptor protein MyD88, which presumably acts in conjunction with other TLR-specific adaptor proteins, such as Tollip and Mal. These adaptor proteins are necessary for the recruitment and activation of different IL-1 receptor-associated kinase family proteins, which further transmit the signal. This leads to activation of the IκB kinase complex and mitogen-activated protein kinases (c-Jun N-terminal kinase/p38), which induce NF-κB and AP-1-dependent gene transcription, respectively. IKK, IκB kinase complex; IRAK, IL-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; MKK, mitogen-activated protein kinase kinase; P, phosphate; Ub, ubiquitin.

FIG. 2.

Ligand specificities of TLRs. Ten different mammalian TLRs have been described, but as yet no function is known for TLR8 and TLR10 (see the text). TLR1 and TLR6 do not signal as separate entities but act in cooperation with TLR2. TLR4 acts in a complex with several other molecules, such as CD14 and MD-2. TLR3, TLR5, and TLR9 exhibit the narrowest ligand specificity. No natural ligands have been described yet for TLR7. LPS, lipopolysaccharide; RSV, respiratory syncytial virus; EDA, extra domain A; HSP60, heat shock protein 60; dsRNA, double-stranded RNA. References are indicated.

FIG. 3.

(A) Drosophila Toll pathway. Drosophila Toll controls dorsoventral axis formation during development and the antifungal and anti-gram-positive organism immune response in the adult fly. In both cases, triggering relies on binding of a host-derived protein, named Spätzle, which is produced as a zymogen that is activated through a serine protease cascade. This proteolytic cascade involves different proteases, both in development and in response to fungal or bacterial challenge. In the Drosophila immune response, the protease cascade is activated by upstream pattern recognition receptors, such as soluble PGRP-SA, which circulates in the hemolymph and recognizes gram-positive pathogen-associated molecular patterns. The pattern recognition receptor responsible for fungal detection has not been characterized yet but may be another member of the PGRP family. Triggering of Toll leads to the recruitment of two adaptor proteins, a MyD88 homolog, Drosophila MyD88 (dMyD88), and tube, a protein with no known homolog in vertebrates. They further transmit the signal to other signaling intermediates and eventually induce the activation of the NF-κB homologue Dif. (B) Drosophila immune deficiency pathway. The immune deficiency (imd) pathway regulates the gram-negative organism immune response in D. melanogaster and was named after one of its intracellular signaling molecules, imd, as the upstream receptor has long been unknown. Recent studies led to the identification of PGRP-LC as the putative gram-negative pattern recognition receptor. PGRP-LC lacks intracellular signaling motifs and might act in concert with a coreceptor or might trigger a protease cascade, which then leads to generation of a ligand for the immune deficiency receptor, analogous to the Toll pathway. Triggering of the immune deficiency receptor induces a signaling cascade which leads to activation of the NF-κB-like transcription factor Relish.