ReviewThe role of Toll-like receptors and Nod proteins in bacterial infection
Introduction
All multicellular organisms have developed mechanisms to ward off potential microbial invaders. Most cope with an innate immune system for defense against infection and striking similarities in terms of structure and function of these systems are found in organisms as diverse as plants, insects and mammals (for review, see Girardin et al., 2002, Staskawicz et al., 2001). Only vertebrates have in addition to the innate system, an adaptive immune system that allows for specific tailoring of the immune response against a particular microbe, and through memory cells, the capacity to react quickly to subsequent infection.
Innate immunity across the animal kingdom relies on the recognition of microbial patterns by sets of germ-line encoded receptors, termed pattern recognition receptors or PRRs. The microbial patterns recognised by PRRs are evolutionary conserved, often structural motifs that are found in a wide range of different microbes, therefore representing prime targets for the detection of infectious agents by the innate immune system with its limited number of receptor molecules. Although termed pathogen-associated molecular patterns or PAMPs, these motifs are not restricted to pathogens since they include such structural molecules as lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, and peptidoglycan (PGN), common to all bacteria, except for Mycoplasma spp. and perhaps Chlamydia spp. Other PAMPs include flagellin, which is the structural component of bacterial flagella, zymosan, which is a component of the cell wall of yeast, and double-stranded RNA from viruses (Barton and Medzhitov, 2003).
On the host side, Toll-like receptors (TLRs) and Nod proteins represent two classes of PRRs in mammals. TLRs are a family of integral membrane proteins while Nod proteins are cytosolic. Both types of PRRs are involved in detecting potentially harmful microbes through PAMP recognition and initiating an inflammatory reaction to combat the infection. There are 10 TLR homologs in the human gene database, and the different PAMPs recognised by individual or combinations of TLRs are beginning to be elucidated (Takeda et al., 2003). For the Nod proteins, Nod1 and Nod2 both recognise bacterial PGN, although requiring distinct motifs of this molecule to achieve detection (Chamaillard et al., 2003a).
Rather than encountering individual PAMPs during an infection, the host cell is confronted with the entire microbe, which may express many different PAMPs at the same time. Therefore, it is important to study the role of these PRRs in the context of bacterial challenge. In this review, we will present an overview of TLR- and Nod-dependent recognition of bacterial ligands with the specific focus on how these proteins and/or their partners play a role in host defense against different microbial challenges.
Section snippets
Toll-like receptors
The study of innate immunity in mammals intensified after the discovery of Toll and the role of this protein in innate immune defense in Drosophila melanogaster. Although first recognized as a receptor involved in embryonic development of the fly (Anderson et al., 1985), it was later demonstrated that Toll deficiency resulted in flies that were highly susceptible to fungal (Lemaitre et al., 1996), and then later, Gram-positive bacterial infections (Lemaitre et al., 1997). The first discovery of
Sites of interaction between host and pathogen
For a successful infection, a pathogen must gain access to the internal environment of the host, either actively invading the tissue or closely interacting with the cells of the host. Most often, the initial encounter between pathogen and host takes place at a mucosal surface. These surfaces, including the respiratory, urogential and gastro-intestinal (GI) tract, are in contact with the external milieu and under constant threat of attack by pathogenic microbes. Epithelial cells line these
PRRs and bacterial infection
During an infection, the host is confronted with an entire organism that may express multiple PAMPs at the same time. Therefore, it is not only important to examine the role of a given PRR in mediating cellular responses towards its known ligand but also to examine the impact of PRR/ligand interaction during whole microbial infections. Furthermore, the mode of challenge is also an important factor to consider, be it infection or treatment of cells ex vivo, “artificial” challenge experiments by
Conclusions
The discovery of TLRs and more recently, the Nod proteins, has opened up the field of innate immunity in mammals. With the characterization of the ligands of these receptors, we can begin to speculate on the potential role of these proteins in pathogen detection. However, it is only with the careful application of mouse knock-out studies with microbial challenge experiments that we will begin to elucidate the true function of these proteins not only in innate immune responses but also in the
Acknowledgements
Work from our laboratories is supported in part by a grant, Programme Transversal de Recherche, from the Institut Pasteur.
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