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Pattern Recognition Receptors The receptors involved in cellular innate recognition of essential structural molecules of microbes depends on germ line encoded molecules often called pattern recognition receptors (PRRs) that do not undergo somatic mutation like the receptors of the adaptive immune system. These PRRs include membrane bound receptors, such as the Type A, B and C scavenger receptors, integrins and the Toll like receptors, C type lectin receptors as well as intracellular receptors like the recently identified nucleotide binding oligomerication domain (NOD) proteins. PRRs are expressed on cells of the innate immune system including macrophages, polymorphonuclear leukocytes, DCs and NK cells but also many other cell types including eptiehlia cells and adipocytes. The response of cells to recognition of microbial products via innate recognition receptors ranges from phagocytosis and related intracellular processes essential for handling ingested microbes to release of a broad range of mediators. These mediators are all involved in the efferent arm of the innate immune response. Important mediators are cytokines, chemokines, antimicrobial peptides, lysozyme, BPI, lactoferrin, proteases, lipases, glycosidases, superoxides, nitric oxide and many others. Extracellular or Membrane PRRs Scavenger receptors:http://www.gahtan.com/cyberlaw/recognize endotoxin, lipoteichic acid and bacterial wall. Intracellular PRRs NLRs (Nod Like Receptors): |
The best-characterized members of the NOD-LRR family are NOD1 and NOD2, which recognize distinct elements of bacterial cell wall peptidoglycan in the cytosol to mount or modulate a proinlfammatory immune response or to promote apoptosis. NOD1/NOD2 are the NBS-LRR proteins involved in intracellular recognition of microbes through specific products derived from peptidoglycans. The NBS-LRR proteins are characterized by 3 structural domains: a C-terminal LRR domain able to sense a microbial motif; an intermediary NBS essential for the ogligomerization of the molecule that is necessary for the signal transduction induced by different N-terminal effeector motifs such as a pyrin domain; and a caspase activating and recruitment domain (CARD) or a baculovirus inhibitor of apoptosis protein repeat domain.
Nod1/Nod2 can sense intracellular bacteria; mice deficient in either show increased sensitivity to infection. Nod1 senses a peptidoglycan motif containing a diaminopimelate containing N-acetylglucosamine-N-acetylmuramic acid tripeptide found mainly in Gram-negative bacterial.
After oligomerization, RIP2 is recruited to Nod through homophilic CARD-CARD interactions. RIP2 is an adaptor protein sharing homology with IRAK and Rip group proteins. Interaction between Nod1 or Nod2 and RIP2 leads to the activation of the NF-kB pathway through the recruitment of the IkB kinase (IKK) complex to the central domain of RIP2.
--NOD1: is an intracellular PRR which detects bacterial when they enter the cytoplasm. For example, once Shagella flexneri or H. pylori, or P. aeruginosa gets into the cytoplasm it activate NOD1 which leads to activation of NF-kB. The motif that is recognized is peptidoglycan from the bacterial cell wall.
--NOD2: As with NOD1, NOD2 recognizes peptidoglycan from the bacterial cell wall. Nod2 senses another peptidoglycan motif, muramyl dipeptide found in both Gram-positive and Gram-negative bacterial. Muramyl dipeptie (MDP) is the minimal PGN motif common to both Gram-positive and Gram-negative bacteria.
--Naip5
In mouse macrophages, the NOD-LRR protein Naip5 (Birc1e) restricts intracellular replication of the opportunistic human pathogen Legionella pneumophila. Naip5 is compirsed of 3 modules: NH2-terminal baculoviral inhibitor of apoptosis repeats, a central NOD domain, and COOH-terminal LRRs. By analogy to other NOD-LRR proteins, the LRR region is thought to recognize microbial products, triggering oligomerization via the NOD domain and activation of a cellular response that is governed by various NH2-terminal effector-binding domains. Whereas virtually all mice are reistant to L. pneumophila the A/J strain encodes a naip5 allele that confers susceptibility to infection.
Other PRRs and Indirect Recognition of viral infection
TLR and c-type lectin receptors recognize PAMP in the extracellular space, but many pathogens reach the cell cytoplams so that host have had to evolve mechanisms to detect pathogens intracellularly. For virus infections, a good example of this is the detection of dsRNA in the cytoplasm by protein kinase R (PKR) activation.
It is also important that the immune system is primed to respond to a nearby infection without coming into direct contact with a virus. Bystander DC can respond to signals originating from other DC or stromal cells that come into contact with PAMP. Some of the inflammatory mediators responisble for this paracrine activaiton are type I IFN and TNFalpha. As viral infection of DC impairs their direct stimulatory capacity in many instances, the implied reliance on cross presentation by uninfected bystander DC becomes all the more important.
