Pattern recognition receptor

Pattern recognition receptors, or PRRs, are proteins expressed by cells of the immune system to identify molecules associated with microbial pathogens or cellular stress.

Molecules recognized
The microbe-specific molecules that are recognized by a given PRR are called PAMPs: pathogen-associated molecular patterns and include bacterial carbohydrates (e.g. lipopolysaccharide or LPS, mannose), nucleic acids (e.g. bacterial or viral DNA or RNA), peptidoglycans and lipotechoic acids (from Gram positive bacteria), N-formylmethionine, lipoproteins and fungal glucans.

Endogenous stress signals are called DAMPs (danger-associated molecular patterns) and include uric acid.

Classification
PRRs are classified according to their ligand specificity, function, localization and/or evolutionary relationships. On the basis of function, PRRs may be divided into endocytic PRRs or signaling PRRs.


 * Signaling PRRs include the large families of membrane-bound Toll-like receptors and cytoplasmic NOD-like receptors.


 * Endocytic PRRs promote the attachment, engulfment and destruction of microorganisms by phagocytes, without relaying an intracellular signal. These PRRs recognize carbohydrates and include mannose receptors of macrophages, glucan receptors present on all phagocytes and scavenger receptors that recognize charged ligands, are found on all phagocytes and mediate removal of apoptotic cells.

Toll-like receptors
Recognition of extracellular or endosomal pathogen-associated molecular patterns is mediated by an array of transmembrane proteins known as toll-like receptors (TLRs). Toll-like receptors were first discovered in Drosophila and are known to trigger a series of mechanisms leading to the synthesis and secretion of cytokines and activation other host defense programs that are crucial to the development of innate or adaptative immune responses. At present, TLRs have been found in many species. In mammals, these receptors have been assigned numbers 1 to 11 (TLR1-TLR11). Interaction of TLRs with their specific PAMP induces NFκB signaling and MAP kinase pathway and therefore the secretion of pro-inflammatory cytokines and co-stimulatory molecules. Molecules released following TLR activation signal to other cells of the immune system making TLRs key elements of innate immunity and adaptive immunity.

The mannose receptor
The mannose receptor (MR) is a PRR primarily present on the surface of macrophages and dendritic cells. It recognizes and binds to carbohydrates on the surfaces of infectious agents and its activation triggers endocytosis and phagocytosis of the microbe. The MR belongs to the multilectin receptor protein group and, like the TLRs, provides a link between innate and adaptive immunity.

NOD Like Receptors
The NOD-like receptors (NLRs) are cytoplasmic proteins that may have a variety of functions in regulation of inflammatory and apoptotic responses. Approximately 20 of these proteins have been found in the mammalian genome and include two major subfamilies called NODs and NALPs, the MHC Class II transactivator (CIITA), and some other molecules (e.g. IPAF and BIRC1). Current understanding suggests some of these proteins recognize endogenous or microbial molecules or stress responses and form oligomers that activate inflammatory caspases (e.g. caspase 1) causing cleavage and activation of important inflammatory cytokines such as IL-1, and/or activate the NF-κB signaling pathway to induce production of inflammatory molecules. The NLR family is known under several different names, including the CATERPILLER (or CLR) or NOD-LRR family.


 * NODS
 * The ligands are currently known for NOD1 and NOD2. NOD1 recognizes a molecule called meso-DAP, that is a peptidoglycan constituent of only Gram negative bacteria.  NOD2 proteins recognize intracellular MDP (muramyl dipeptide), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria.  NODS transduce signals in the pathway of NF-κB and MAP kinases via the serine-threonine kinase called RIP2.  NOD proteins are so named as they contain a nucleotide-binding oligomerization domain which binds nucleotide triphosphate.  NODs signal via N-terminal CARD domains to activate downstream gene induction events, and interact with microbial molecules by means of a C-terminal leucine-rich repeat (LRR) region.


 * NALPS
 * Like NODs, these proteins contain C-terminal LRRs, which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens. Also like NODs, these proteins also contain a nucleotide binding site (NBS) for nucleotide triphosphates. Interaction with other proteins (e.g. the adaptor molecule ASC) is mediated via N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (called NALP1 to NALP14).  Mutations in NALP3 are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease. Activators of NALP3 include muramyl dipeptide, bacterial DNA, ATP, toxins, double stranded RNA, paramyxoviruses and uric acid crystals.  Although these specific molecules have been shown to activate NALP3, it remains unclear whether this is due to direct binding or due to cellular stress induced by these agents.


 * Other NLRs
 * Other NLRs such as Ipaf and NAIP5/Birc1e have also been shown to activate caspase-1 in response to Salmonella and Legionella.

RNA Helicases
Intracellular recognition of viral double-stranded (ds) and single stranded RNA has been shown to be mediated by a group of RNA Helicases which in turn recruit factors via twin N-terminal CARD domains to activate antiviral gene programs. Three such helicases have been described in mammals--RIG-I and MDA5 (recognizing 5'triphosphate-RNA and dsRNA, respectively), which activate antiviral signaling, and LGP2, which appears to act as a dominant-negative inhibitor.

Plant R Proteins
Plants contain a significant number of PRRs that share remarkable structural and functional similarity with those found in higher organisms such as drosophila and mammals. As can be predicted, these proteins activate host defense mechanisms in response to infection. Several characterized proteins feature NBS and LRR domains, as well as some conserved interaction domains such as the TIR. As in mammalian systems, controversy exists as to whether R proteins recognize discreet ligands via their LRRs, are activated by cellular stress, or a combination of the two.

Secreted PRRs
A number of PRRs do not remain associated with the cell that produces them. Complement receptors, collectins, pentraxin proteins such as serum amyloid and C-reactive protein, lipid transferases and peptidoglycan recognition proteins (PGRs) are all secreted proteins. One very important collectin is mannan-binding lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins.