UNDERSTANDING THE PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPs) AND PATTERN RECOGNITION MOLECULES (PRMs)

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Pathogen-associated molecular patterns (PAMPs) are structural components common to a particular group of pathogen or infectious disease agents. PAMPs are often macromolecules and include polysaccharides, proteins, nucleic acids, or even lipids. The lipopolysaccharide (LPS) of the Gram negative bacterial cell wall is an excellent example of PAMP. Interaction between PAMPs and host PRMs are integral components of the innate immune response. PRMs interact with PAMPs shared by various pathogens, activating complement and phagocytes to target and destroy pathogens. These interactions initiate signal transduction cascades that activate effector cells in the host.

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Pattern-recognition molecules (PRMs) are a group of soluble and membrane-bound host proteins that interact with PAMPs. The PAMP recognized by mannan-binding lectin is the sugar mannose, found as a repeating subunit in bacterial polysaccharides (mannose on mammalian cells is inaccessible to mannan-binding lectin). Complements binds to a variety of pathogen cell surface components. C-reactive protein, another PRM, is an acute phase protein produced by the liver in response to inflammation. C-reactive protein interacts with the phosphorylcholine macromolecules of Gram positive bacterial cell walls. These PRMs all target pathogen surface PAMPs, leading to lysis of the targeted cell or opsonization.

Evolutionary conserved, membrane-bound PRMs are found on the surfaces of macrophages, monocytes, dendritic cells, and neutrophils. These cells initiate phagocytosis (the engulfment and destruction of the pathogen). PRMs were first recognized in Drosophila (the fruit fly), where they were called Toll receptors. Structural, functional, and evolutionary homologs of the Toll receptors, called Toll-like receptors (TLRs), are widely expressed in mammalian phagocytes. .at least nine (9) TLRs in humans interact with a variety of cell surface and soluble PAMPs from viruses, bacteria, and fungi.

Several TLRs interact with more than one PAMP. For example, TLR-4 is part of the innate immune response to Gram negative LPS and also responds to a host-response molecule called heat shock protein. Neither LPS nor heat shock protein interacts directly with the TLR-4, but rather interacts via a receptor protein that, in turn, interacts with TLR-4. In other cases, the TLR binds directly to the PAMP, as is the case for TLR-5 and its target, flagellin. Interaction of a PAMP with the TLR triggers a transmembrane signal transduction event, initiating transcription of DNA that leads to the synthesis of specific proteins and activation of the phagocytes. Activation can result in enhanced phagocytosis and killing of pathogens or contribute to inflammation.  

Drosophila Toll Receptors – An Ancient Response to Infections

Multicellular organisms such as invertebrates and plants lack adaptive immunity but have a well-developed innate response to a wide variety of pathogens. Response to pathogens by the fruit fly, Drosophila melanogaster (Figure 1) have provided insight into innate immune mechanisms in many other groups of organisms. Several proteins required for fruit fly development are also important receptors for recognizing invading bacteria, functioning as PRMs that interact with PAMPs on the macromolecules produced by the pathogen. The best example of a PRM is Drosophila Toll, a transmembrane protein involved in dorso-ventral axis formation as well as in the innate immune response of the fly.

Figure 1. Drosophila melanogaster, the common fruit fly.

Toll immune signaling is initiated by the interaction of a pathogen or its components with the Toll protein displayed on the surface of phagocytes. Drosophila Toll, however, does not interact directly with the pathogen. Signal transduction events start with the binding of a PAMP such as the lipopolysaccharide (LPS) of Gram negative bacteria by one or more accessory proteins. The LPS-accessory protein complex then binds to Toll. The membrane-integrated Toll protein initiates a signal transduction cascade, activating a nuclear transcription factor and inducing transcription of several genes that encode antimicrobial peptide. Toll-associated transcription factors include expression of antimicrobial peptides, including drosomycin, an antifungal peptide, diptericin, active against Gram negative bacteria, and defensin, active against Gram positive bacteria.

The peptides, produced in the liver-like fat body of Drosophila, are released into the fly’s circulatory system where they interact with the target organism and cause cell lysis. Structurally, the Toll proteins are related to lectins, a group of proteins found in virtually all multicellular organisms, including vertebrates and plants. Lectins interact specifically with certain oligosaccharide monomers. In humans, Toll-like receptors (TLRs) react with a wide variety of PAMPs. As with drosophila Toll, human TLR-4 provides innate immunity against the Gram negative bacteria through indirect interactions with LPS, initiating a kinase signal cascade and activating the nuclear transcription factor NFƙB. NFƙB activates transcription of cytokines and other phagocyte proteins involved in the host response.

Drosophila Toll is a functional, evolutionary, and structural ancestor to the Toll-like receptors in higher vertebrates, including humans. Toll and its homologs are evolutionarily ancient, highly conserved components of the innate immune system in animals and have been found in plants.

Further reading

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of Microorganisms, 12th edition. Pearson Benjamin Cummings Inc, USA.

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