Although there is no doubt that TLRs are essential to efficient recognition and eradication of pathogens, it is worth mentioning that the innate immune system has evolved TLR-independent pathways that, in parallel, provide immune-specific protection for the host. Some of these pathways are rather well established and involve, for instance, the complement system, or NK cell receptors (reviewed by [73, 74]). Other pathways are just starting to emerge and thus far limited information is available as to how they contribute to bacterial sensing.
While TLRs do not sense peptidoglycan, derivatives of peptidoglycan are detected through a pathway requiring nucleotide-binding oligomerization domain (Nod) proteins. The family of Nod proteins include Nodi and Nod2 (Fig. 3). These proteins are expressed in the cytosol and whether directly or indirectly, mediate recognition of structurally distinct types of peptidoglycan. Peptidoglycan consists of gly-can chains containing alternating N-acetylglucosamine (GlcNAc) and N-acetylmu-ramic acid (MurNAc) sugars that are coupled by short peptides. Whereas Nodi is activated by the PGN degradation product GlcNAc-MurNAc-L-Ala-y-D-Glu-meso-diaminopimelic acid and primarily senses Gram-negative bacteria, Nod2 is able to recognize muramyl dipeptide, a minimal structure present in Gram-positive and Gram-negative bacteria. Both Nodi and Nod2 contain caspase-activating and recruitment domains (CARD), which are thought to interact with the CARD domain of a serine/threonine kinase called RIP2 (also known as RICK or CAR-DIAK) . Ultimately, this leads to the phosphorylation of IKBa and subsequent translocation of NF-kB. Genetic variation in the genes encoding NOD proteins in humans has been associated with inflammatory diseases such as Crohn's disease [76, 77], and recently, an infectious phenotype (susceptibility to enteric L. monocytogenes infection) has been observed in Nod2 knockout mice . This subject is discussed further in the chapter by Fukata et al. in this book.
Another TLR-independent pathway involved in the recognition of bacteria is mediated by the CDld-dependent activation of NKT cells. NKT cells recognize endogenous or bacterially derived glycosphingolipids that are presented by DCs via the CD1d major histocompatibility complex-like molecules that have evolved to specifically capture lipid antigens. The CD1d activated NKT cells thus comprises an alternative innate pathway that leads to early recognition and production of inflammatory cytokines such as IFN-y. Certain Gram-negative, LPS-negative bacterial species such as Ehrlichia muris and Sphingomonas "escape" TLR-recognition and the host response to infection by these bacterial species depends exclusively upon recognition via the CD1d pathway [78, 79]. Mice lacking NKT cells have been shown to be defective in efficient clearing of Sphingomonas from the liver, confirming the importance of this pathway for eradication of this specific bacterial strain.
Although it is clear that TLRs are a major group of receptors involved in the recognition of bacteria, other innate immune pathways have shown to contribute to an efficient eradication of bacteria. Whereas some pathways act primarily in synergy with TLRs, other pathways can act independently with the host relying exclusively on these pathways to eliminate pathogens. The relative contribution of these pathways will be a major focus for future studies, and can be expected to complement the unique inflammatory "signature" that is required for different pathogens.
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