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Results for “Innate Immunity Recognition”

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PubMed2003

Toll-like receptors and their role in experimental models of microbial infection.

Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

Animals↗
PubMed2004

Peptidoglycan recognition proteins: on and off switches for innate immunity.

Insects rely on innate immune mechanisms to defend themselves against microbes. The inducible anti-microbial peptides constitute an important arm of this defense. In Drosophila, the Toll and the Imd pathways are the major routes to induce the peptides, and it has become clear that to a certain extent, these pathways can discriminate between different microbes and mount an appropriate response to eliminate the intruder. This review discusses the proteins responsible for this discriminatory recognition, the peptidoglycan recognition proteins (PGRPs). The serum protein PGRP-SA triggers a humoral cascade of proteases upon infection by certain gram-positive bacteria to activate the Toll pathway. The membrane-bound receptor PGRP-LC activates the Imd pathway in response to certain gram-negative bacteria or their peptidoglycans. Other PGRPs have enzymatic activity, cleaving lactylamide bonds in peptidoglycan to eliminate its immunogenicity, thus turning off the immune response. The PGRP family is conserved from insects to man. Short mammalian PGRP variants are synthesized in neutrophils and stored in granules. These PGRPs seem to influence the survival of phagocytosed non-pathogenic bacteria. Long PGRP variants are expressed in the liver and secreted into the bloodstream where their peptidoglycan-degrading activity might serve scavenger functions.

Amino Acid Sequence↗
PubMed2006

Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs).

The innate immune system constitutes the first line of defense against microorganisms in both vertebrates and invertebrates. Although much progress has been made toward identifying key receptors and understanding their role in host defense, far less is known about how these receptors recognize microbial ligands. Such studies have been severely hampered by the need to purify ligands from microbial sources and a reliance on biological assays, rather than direct binding, to monitor recognition. We used synthetic peptidoglycan (PGN) derivatives, combined with microcalorimetry, to define the binding specificities of human and insect peptidoglycan recognition proteins (PGRPs). We demonstrate that these innate immune receptors use dual strategies to distinguish between PGNs from different bacteria: one based on the composition of the PGN peptide stem and another that senses the peptide bridge crosslinking the stems. To pinpoint the site of PGRPs that mediates discrimination, we engineered structure-based variants having altered PGN-binding properties. The plasticity of the PGRP-binding site revealed by these mutants suggests an intrinsic capacity of the innate immune system to rapidly evolve specificities to meet new microbial challenges.

Animals↗
PubMed2005

Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner.

Recognition of pathogens by the innate immune system is mediated by pattern recognition receptors (PRRs), which recognize specific molecular structures of the infectious agents and subsequently trigger expression of genes involved in host defense. Toll-like receptors (TLRs) represent a well-characterized class of membrane-bound PRRs, and the RNA helicase retinoic acid inducible gene I (RIG-I) has recently been described as a novel cytoplasmic PRR recognizing double-stranded RNA (dsRNA). Here we show that activation of signal transduction and induction of cytokine expression by the paramyxovirus Sendai virus is dependent on virus replication and involves PRRs in a cell-type-dependent manner. While nonimmune cells relied entirely on recognition of dsRNA through RIG-I for activation of an antiviral response, myeloid cells utilized both the single-stranded RNA sensing TLR7 and TLR8 and dsRNA-dependent mechanisms independent of RIG-I, TLR3, and dsRNA-activated protein kinase R to trigger this response. Therefore, there appears to be a large degree of cell-type specificity in the mechanisms used by the host to recognize infecting viruses.

Animals↗
PubMed2005

Mosquito innate immunity: involvement of beta 1,3-glucan recognition protein in melanotic encapsulation immune responses in Armigeres subalbatus.

Beta 1,3-glucan recognition proteins (GRP) have specific affinity for beta 1,3-glucan, a component on the surface of fungi and bacteria. By interacting with beta 1,3-glucan, GRP initiates activation of prophenoloxidase, a key enzyme in the signaling pathway leading to melanotic encapsulation in invertebrates. In this study, we characterize a novel hemocyte-specific GRP from the mosquito, Armigeres subalbatus (AsGRP). The 1.57 kb cDNA clone encodes a 499 deduced amino acid sequence, which contains a region that displays significant similarity to the glucanase-like regions of other GRPs and Gram-negative bacteria binding proteins found in other organisms. AsGRP is constitutively expressed in the hemolymph of adult female mosquitoes, and is upregulated following challenge with Escherichia coli, Micrococcus luteus, and the filarial worm Dirofilaria immitis. AsGRP specifically recognizes curdlan (insoluble beta 1,3-glucan), but not mannose or N-acetyl-D-glucosamine. AsGRP binds a low percentage of E. coli, most M. luteus and D. immitis microfilariae. AsGRP double-stranded RNA interference strongly inhibits melanotic encapsulation of D. immitis in Ar. subalbatus. These results suggest that AsGRP has the capacity to bind to a variety of pathogens, functions as a pattern recognition receptor, and is required for effective melanotic encapsulation immune responses in Ar. subalbatus.

Acetylglucosamine↗
PubMed2005

Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity.

Innate immune responses to bacteria require cooperative interactions between host recognition molecules and phagocytes. The peptidoglycan recognition proteins (PGRPs) are a large group of proteins found in insects and mammals that bind to bacterial peptidoglycan (PGN). PGRP-S is located with other antimicrobial proteins, such as lysozyme, in the granules of human neutrophils. Whereas both PGRP-S and lysozyme recognize PGN, the exact binding specificity of human PGRP-S, its functional activity, and its potential synergy with other neutrophil-derived bactericidal proteins such as lysozyme have not been determined. Here we show that human PGRP-S binds to and inhibits the growth of Staphylococcus aureus (containing lysine-type PGN) and Escherichia coli (containing mesodiaminopimelic acid-type PGN). The binding affinity and thus antimicrobial activity of PGRP-S is determined by the third amino acid in the PGN stem peptide. Furthermore, the antimicrobial effect of PGRP-S against E coli is synergistic with lysozyme, and lysozyme and PGRP-S colocalize in neutrophil extracellular traps (NETs), suggesting that these granule-derived proteins act together to kill bacteria trapped in the NETs. Taken together, these results indicate that human PGRP-S plays a role in innate immunity in the context of neutrophils by contributing to the killing of intracellular and extracellular bacteria.

Anti-Infective Agents↗
PubMed2006

[Defense mechanism against respiratory infection].

Most of acute respiratory diseases are caused by infection with various viruses, bacteria and other microorganisms; a mixed infection with these pathogens often results in exacerbation of the disease. In addition to nonspecific protective mechanisms that constantly function in the respiratory tracts, innate and adaptive immunities play important roles in the protection of these pathogens. Secretory IgA and/or cytotoxic T cells in the mucus may be the most effective protection machineries of the adaptive immune systems. Recently, it has been proven that Toll-like receptors, each of which recognizes a conserved structure of pathogens, are the key molecules of the innate immune systems; this recognition step is considered a prerequisite for the adaptive immunity to function in the respiratory tracts.

Humans↗
PubMed2004

Toll-like receptors and dendritic cells: for whom the bug tolls.

Recognition of molecular signatures of potential pathogens via toll-like receptors (TLRs) activates dendritic cells (DC), leading to the initiation of adaptive immunity. TLR signalling in DC causes an increase in display of MHC peptide ligands for T cell recognition, upregulation of co-stimulatory molecules important for T cell clonal expansion and secretion of immunomodulatory cytokines, which direct T cell differentiation into effectors. Remarkably, ligation of distinct TLRs can trigger differential cytokine production in a single DC type or result in different cytokines in distinct DC sub-types. Studying the complexity of DC responses to TLR ligands illuminates the link between innate recognition and adaptive immunity, paving the way for improved vaccines and strategies to induce tolerance to autoantigens or allografts.

Animals↗
PubMed2000

Self-recognition of CD1 by gamma/delta T cells: implications for innate immunity.

The specificity of immunoglobulins and alpha/beta T cell receptors (TCRs) provides a framework for the molecular basis of antigen recognition. Yet, evolution has preserved a separate lineage of gamma/delta antigen receptors that share characteristics of both immunoglobulins and alpha/beta TCRs but whose antigens remain poorly understood. We now show that T cells of the major tissue gamma/delta T cell subset recognize nonpolymorphic CD1c molecules. These T cells proliferated in response to CD1+ presenter cells, lysed CD1c+ targets, and released T helper type 1 (Th1) cytokines. The CD1c-reactive gamma/delta T cells were cytotoxic and used both perforin- and Fas-mediated cytotoxicity. Moreover, they produced granulysin, an important antimicrobial protein. Recognition of CD1c was TCR mediated, as recognition was transferred by transfection of the gamma/delta TCR. Importantly, all CD1c-reactive gamma/delta T cells express V delta 1 TCRs, the TCR expressed by most tissue gamma/delta T cells. Recognition by this tissue pool of gamma/delta T cells provides the human immune system with the capacity to respond rapidly to nonpolymorphic molecules on professional antigen presenting cells (APCs) in the absence of foreign antigens that may activate or eliminate the APCs. The presence of bactericidal granulysin suggests these cells may directly mediate host defense even before foreign antigen-specific T cells have differentiated.

Amino Acid Sequence↗
PubMed2003

Toll-like receptors: networking for success.

The innate immune system is essential for host defense and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells such as macrophages and dendritic cells, diverse signaling pathways are activated that combine to define inflammatory responses that direct sterilization of the threat and/or orchestrate development of the adaptive immune response. Innate immune signaling must be carefully controlled, and regulation comes in part from interactions between activating and inhibiting signaling receptors. Toll-like receptors (TLR) have recently emerged as key receptors responsible for recognizing specific conserved components of microbes including lipopolysaccharides from Gram-negative bacteria, CpG DNA, and flagellin. Full activation of inflammatory responses by TLR may require the assembly of receptor signaling complexes including other transmembrane proteins that may influence signal transduction. In addition to TLR, many additional receptors participate in innate recognition of microbes, and recent studies demonstrate strong interactions between signaling through these receptors and signaling through TLR. Useful models for these interacting signaling pathways are now emerging and should pave the way for understanding the molecular mechanisms that drive the rich diversity of inflammatory responses.

Carrier Proteins↗
PubMed2002

Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines.

Pattern recognition receptors (PRR) play an important roll in immediate responses to different conserved molecules produced by microbes. In this paper we describe the cloning of the mouse homolog of Toll-like receptor (TLR) 3, and present an analysis of the expression of this gene in innate and adaptive immune cell lines. We also performed a broad expression study on these cells of other TLR, including TLR family members whose expression pattern is not known, i.e. TLR7. The analysis was done in order to understand, and possibly predict, how innate and adaptive immune cells respond to microbial pattern antigens. This first large-scale analysis of immune cell TLR expression in the mouse reveals that cells of the innate immune system express a broader number of TLR than cells of the adaptive immune system, supporting preconceptions concerning the hierarchy of immune cells involved in direct pathogen recognition. Additionally, the expression of TLR transcripts by mast cells, neutrophils and microglial cells observed here suggests that pathogen-associated molecular pattern molecules could induce activation of these cells through TLR. Finally, the mouse homolog of human TLR3 identified here may, like its human counterpart, be an exceptional TLR molecule due to its lack of a conserved proline residue seen to be involved in existing TLR signaling capabilities found in other TLR family members.

Amino Acid Sequence↗
PubMed2006

Bovine peptidoglycan recognition protein-S: antimicrobial activity, localization, secretion, and binding properties.

Peptidoglycan (PGN) recognition proteins (PGRPs) are pattern recognition molecules of innate immunity that are conserved from insects to humans. Various PGRPs are reported to have diverse functions: they bind bacterial molecules, digest PGN, and are essential to the Toll pathway in Drosophila. One family member, bovine PGN recognition protein-S (bPGRP-S), has been found to bind and kill microorganisms in a PGN-independent manner, raising questions about the identity of the bPGRP-S ligand. Addressing this, we have determined the binding and microbicidal properties of bPGRP-S in a range of solutions approximating physiologic conditions. In this study we show that bPGRP-S interacts with other bacterial components, including LPS and lipoteichoic acid, with higher affinities than for PCP, as determined by their abilities to inhibit bPGRP-S-mediated killing of bacteria. Where and how PGRPs act in vivo is not yet clear. Using Immunogold electron microscopy, PGRP-S was localized to the dense/large granules of naive neutrophils, which contain the oxygen-independent bactericidal proteins of these cells, and to the neutrophil phagolysosome. In addition, Immunogold staining and secretion studies demonstrate that neutrophils secrete PGRP-S when exposed to bacteria. Bovine PGRP-S can mediate direct lysis of heat-killed bacteria; however, PGRP-S-mediated killing of bacteria is independent of this activity. Evidence that bPGRP-S has multiple activities and affinity to several bacterial molecules challenges the assumption that the PGRP family of proteins recapitulates the evolution of TLRs. Mammalian PGRPs do not have a single antimicrobial activity against a narrow range of target organisms; rather, they are generalists in their affinity and activity.

Animals↗
PubMed2006

Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity.

The purpose of physiological cell death is the noninflammatory clearance of cells that have become inappropriate or nonfunctional. Consistent with this function, the recognition of apoptotic cells by professional phagocytes, including macrophages and dendritic cells, triggers a set of potent anti-inflammatory responses manifest on multiple levels. The immediate-early inhibition of proinflammatory cytokine gene transcription in the phagocyte is a proximate consequence of recognition of the apoptotic corpse, independent of subsequent engulfment and soluble factor involvement. Here, we show that recognition is linked to a characteristic signature of responses, including MAPK signaling events and the ablation of proinflammatory transcription and cytokine secretion. Specific recognition and response occurs without regard to the origin (species, tissue type, or suicidal stimulus) of the apoptotic cell and does not involve Toll-like receptor signaling. These features mark this as an innate immunity fundamentally distinct from the discrimination of "self" versus "other" considered to be the hallmark of conventional immunity. This profound unconventional innate immune discrimination of effete from live cells is as ubiquitous as apoptotic cell death itself, manifest by professional and nonprofessional phagocytes and nonphagocytic cell types alike. Innate apoptotic immunity provides an intrinsic anti-inflammatory circuit that attenuates proinflammatory responses dynamically and may act systemically as a powerful physiological regulator of immunity.

Animals↗
PubMed2006

The role of toll-like receptors in solid organ transplantation.

Toll-like receptors (TLR) are critical sentinels of the host innate immune system. Prior evidence has clearly demonstrated that these receptors are essential to immune recognition of invading pathogens. However, there is emerging evidence that TLR signaling participates in inflammation that is not driven by microorganisms. In the setting of solid organ transplantation, there is accumulating evidence, both in experimental and clinical studies, that TLR signaling is involved in the immune recognition of allografts. Further investigation of how innate immunity impacts solid organ transplantation will likely lead to improved therapeutics for transplant recipients.

Humans↗
PubMed2006

Calcium is not required for immulectin-2 binding, but protects the protein from proteinase digestion.

Mammalian C-type lectins are calcium-dependent carbohydrate-binding proteins. They serve as cell adhesion molecules in cell-cell interactions, or function as pattern-recognition receptors in innate immunity. Calcium is a direct ligand for carbohydrate binding in mammalian C-type lectins such as mannose-binding proteins and macrophage mannose receptor. In the tobacco hornworm Manduca sexta, a group of lectins named immulectins have been discovered. Each immulectin contains dual carbohydrate-recognition domains. Previously, we showed that immulectin-2 (IML-2) binds to a bacterial lipopolysaccharide, and agglutination of Escherichia coli cells by IML-2 is calcium dependent. In this study, we demonstrated that IML-2 bound to bacterial lipid A, smooth and rough mutants of lipopolysaccharide, lipoteichoic acid and peptidoglycan, as well as to fungal mannan and beta-1, 3-glucan (laminarin and curdlan). Binding of IML-2 to microbial components was calcium independent, and was increased by addition of spermine, a polyamine. In addition, plasma IML-2 bound to mannan-agarose independent of calcium. But trypsin digestion of IML-2 was inhibited in the presence of calcium. Our results suggest that calcium is not required for IML-2 binding but protects IML-2 from trypsin digestion.

Agglutination↗
PubMed2005

Innate autoimmunity.

The adaptive immune system has evolved highly specific pattern recognition proteins and receptors that, when triggered, provide a first line of host defense against pathogens. Studies reveal that these innate recognition proteins are also self-reactive and can initiate inflammation against self-tissues in a similar manner as with pathogens. This specific event is referred to as "innate autoimmunity." In this review, we describe two classes of autoimmune responses, that is, reperfusion injury and fetal loss syndrome, in which the recognition and injury are mediated by innate immunity. Both disorders are common and are clinically important. Reperfusion injury (RI) represents an acute inflammatory response after a reversible ischemic event and subsequent restoration of blood flow. Findings that injury is IgM and complement dependent and that a single natural antibody prepared from a panel of B-1 cell hybridomas can restore injury in antibody-deficient mice suggest that RI is an autoimmune-type disorder. Fetal loss syndrome is also an antibody- and complement-dependent disorder. Although both immune and natural antibodies are likely involved in recognition of phospholipid self-antigens, inhibition of the complement pathway in rodent models can block fetal loss. As new innate recognition proteins and receptors are identified, it is likely that innate responses to self represent frequent events and possibly underlie many of the known chronic autoimmune disorders normally attributable to dysregulation of adaptive immunity.

Animals↗
PubMed2004

Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4.

Molecular and genetic studies have demonstrated that members of the Toll-like receptor (TLR) family are critical innate immune receptors. TLRs are recognition receptors for a diverse group of microbial ligands including bacteria, fungi, and viruses. This study demonstrates that distinct TLRs are responsible for the recognition of Helicobacter lipopolysaccharide (LPS) versus intact Helicobacter bacteria. We show that the cytokine-inducing activity of Helicobacter LPS was mediated by TLR4; i.e., TLR4-deficient macrophages were unresponsive to Helicobacter pylori LPS. Surprisingly, the cytokine response to whole Helicobacter bacteria (H. pylori, H. hepaticus, and H. felis) was mediated not by TLR4 but rather by TLR2. Studies of HEK293 transfectants revealed that expression of human TLR2 was sufficient to confer responsiveness to intact Helicobacter bacteria, but TLR4 transfection was not sufficient. Our studies further suggest that cag pathogenicity island genes may modulate the TLR2 agonist activity of H. pylori as cagA+ bacteria were more active on a per-cell basis compared to cagA mutant bacteria for interleukin-8 (IL-8) cytokine secretion. Consistent with the transfection studies, analysis of knockout mice demonstrated that TLR2 was required for the cytokine response to intact Helicobacter bacteria. Macrophages from both wild-type and TLR4-deficient mice produced a robust cytokine secretion response (IL-6 and MCP-1) when stimulated with intact Helicobacter bacteria. In contrast, macrophages from TLR2-deficient mice were profoundly unresponsive to intact Helicobacter stimulation, failing to secrete cytokines even at high (100:1) bacterium-to-macrophage ratios. Our studies suggest that TLR2 may be the dominant innate immune receptor for recognition of gastrointestinal Helicobacter species.

Animals↗