Prokaryotic innate immunity through pattern recognition of conserved viral proteins.

Many organisms have evolved specialized immune pattern-recognition receptors, including nucleotide-binding oligomerization domain-like receptors (NLRs) of the STAND superfamily that are ubiquitous in plants, animals, and fungi. Although the roles of NLRs in eukaryotic immunity are well established, it is unknown whether prokaryotes use similar defense mechanisms. Here, we show that antiviral STAND (Avs) homologs in bacteria and archaea detect hallmark viral proteins, triggering Avs tetramerization and the activation of diverse N-terminal effector domains, including DNA endonucleases, to abrogate infection. Cryo-electron microscopy reveals that Avs sensor domains recognize conserved folds, active-site residues, and enzyme ligands, allowing a single Avs receptor to detect a wide variety of viruses. These findings extend the paradigm of pattern recognition of pathogen-specific proteins across all three domains of life.

LysM receptors in Coffea arabica: Identification, characterization, and gene expression in response to Hemileia vastatrix.

Pathogen-associated molecular patterns (PAMPs) are recognized by pattern recognition receptors (PRRs) localized on the host plasma membrane. These receptors activate a broad-spectrum and durable defense, which are desired characteristics for disease resistance in plant breeding programs. In this study, candidate sequences for PRRs with lysin motifs (LysM) were investigated in the Coffea arabica genome. For this, approaches based on the principle of sequence similarity, conservation of motifs and domains, phylogenetic analysis, and modulation of gene expression in response to Hemileia vastatrix were used. The candidate sequences for PRRs in C. arabica (Ca1-LYP, Ca2-LYP, Ca1-CERK1, Ca2-CERK1, Ca-LYK4, Ca1-LYK5 and Ca2-LYK5) showed high similarity with the reference PRRs used: Os-CEBiP, At-CERK1, At-LYK4 and At-LYK5. Moreover, the ectodomains of these sequences showed high identity or similarity with the reference sequences, indicating structural and functional conservation. The studied sequences are also phylogenetically related to the reference PRRs described in Arabidopsis, rice, and other plant species. All candidates for receptors had their expression induced after the inoculation with H. vastatrix, since the first time of sampling at 6 hours post-inoculation (hpi). At 24 hpi, there was a significant increase in expression, for most of the receptors evaluated, and at 48 hpi, a suppression. The results showed that the candidate sequences for PRRs in the C. arabica genome display high homology with fungal PRRs already described in the literature. Besides, they respond to pathogen inoculation and seem to be involved in the perception or signaling of fungal chitin, acting as receptors or co-receptors of this molecule. These findings represent an advance in the understanding of the basal immunity of this species.

Two cGAS-like receptors induce antiviral immunity in Drosophila.

In mammals, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide 2'3'-cGAMP in response to cytosolic DNA and this triggers an antiviral immune response. cGAS belongs to a large family of cGAS/DncV-like nucleotidyltransferases that is present in both prokaryotes1 and eukaryotes2-5. In bacteria, these enzymes synthesize a range of cyclic oligonucleotides and have recently emerged as important regulators of phage infections6-8. Here we identify two cGAS-like receptors (cGLRs) in the insect Drosophila melanogaster. We show that cGLR1 and cGLR2 activate Sting- and NF-κB-dependent antiviral immunity in response to infection with RNA or DNA viruses. cGLR1 is activated by double-stranded RNA to produce the cyclic dinucleotide 3'2'-cGAMP, whereas cGLR2 produces a combination of 2'3'-cGAMP and 3'2'-cGAMP in response to an as-yet-unidentified stimulus. Our data establish cGAS as the founding member of a family of receptors that sense different types of nucleic acids and trigger immunity through the production of cyclic dinucleotides beyond 2'3'-cGAMP.

RRGPredictor, a set-theory-based tool for predicting pathogen-associated molecular pattern receptors (PRRs) and resistance (R) proteins from plants.

In plant-pathogen interactions, plant immunity through pathogen-associated molecular pattern receptors (PAMPs) and R proteins, also called pattern recognition receptors (PRRs), occurs in different ways depending on both plant and pathogen species. The use and search for a structural pattern based on the presence and absence of characteristic domains, regardless of their disposition within a sequence, could be efficient in identifying PRRs proteins. Here, we develop a method mainly based on text mining and set theory to identify PRR and R genes that classify them into 13 categories based on the presence and absence of the main domains. Analyzing 24 plant and algae genomes, we showed that the RRGPredictor was more efficient, specific and sensitive than other tools already available, and identified PRR proteins with variations in size and in domain distribution throughout the sequence. Besides an easy identification of new plant PRRs proteins, RRGPredictor provided a low computational cost.

Pattern recognition receptors in Drosophila immune responses.

Insects, which lack the adaptive immune system, have developed sophisticated innate immune system consisting of humoral and cellular immune responses to defend against invading microorganisms. Non-self recognition of microbes is the front line of the innate immune system. Repertoires of pattern recognition receptors (PRRs) recognize the conserved pathogen-associated molecular patterns (PAMPs) present in microbes, such as lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA) and ß-1, 3-glucans, and induce innate immune responses. In this review, we summarize current knowledge of the structure, classification and roles of PRRs in innate immunity of the model organism Drosophila melanogaster, focusing mainly on the peptidoglycan recognition proteins (PGRPs), Gram-negative bacteria-binding proteins (GNBPs), scavenger receptors (SRs), thioester-containing proteins (TEPs), and lectins.

International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease.

Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.

Implication of pattern-recognition receptors in cardiovascular diseases.

SIGNIFICANCE: Pattern-recognition receptors (PRRs) are a family of receptors that are used to detect pathogen-associated molecular patterns or damage-associated molecular patterns, which initiate immune responses to resolve infections and repair damaged tissues. Abnormalities in PRR activation will unavoidably lead to excessive inflammation. RECENT ADVANCES: Although multiple pathophysiological processes are involved in cardiovascular disease, recent studies have highlighted the importance of innate PRRs, in particular, Toll-like receptors and nucleotide-binding oligomerization domain-like receptors, in mediating inflammatory responses and cardiovascular function. CRITICAL ISSUES: The functional roles and regulatory mechanisms of PRRs in cardiovascular diseases are still largely unknown. In particular, controversies exist on the certainty of these detrimental or beneficial effects of some PRRs in different diseased states or different experimental animal models. FUTURE DIRECTIONS: Considering that the molecular mechanisms for individual PRR to regulate cellular function are complex and multiple PRRs are activated simultaneously or synergistically, a better understanding of the function of individual PRRs and the interplay of PRRs will provide unexpected opportunities to develop new therapies for cardiovascular disease by modulation of an innate immune system.

The multifaceted nature of NLRP12.

NLRs are a class of cytoplasmic PRRs with various functions, ranging from pathogen/damage sensing to the modulation of inflammatory signaling and transcriptional control of MHC and related genes. In addition, some NLRs have been implicated in preimplantation and prenatal development. NLRP12 (also known as RNO, PYPAF7, and Monarch-1), a member of the family containing an N-terminal PYD, a NBD, and a C-terminal LRR region, is one of the first described NLR proteins whose role remains controversial. The interest toward NLRP12 has been boosted by its recent involvement in colon cancer, as well as in the protection against some severe infections, such as that induced by Yersinia pestis, the causative agent of plague. As NLRP12 is mainly expressed by the immune cells, and its expression is down-regulated in response to pathogen products and inflammatory cytokines, it has been predicted to play a role as a negative regulator of the inflammatory response. Herein, we present an overview of the NLR family and summarize recent insights on NLRP12 addressing its contribution to inflammatory signaling, host defense, and carcinogenesis.

Primary immunodeficiencies of pattern recognition receptors.

Primary immunodeficiencies (PIDs) are severe defects in the capacity of the host to mount a proper immune response, and are characterized by an increased susceptibility to infections. Although classical immunodeficiencies have been characterized based on broad defects in cell populations (e.g. T/B cells or polymorphonuclear leukocytes) or humoral factors (e.g. antibodies or complement), specific immune defects based on well-defined molecular targets have been described more recently. Among these, genetic defects in pattern recognition receptors (PRRs), leading to impaired recognition of invading pathogens by the innate immune system, play an important role in specific defects against human pathogens. Defects have been described in three of the major families of PRRs: the Toll-like receptors, the C-type lectin receptors and the nucleotide-binding domain leucine-rich repeat-containing receptors. By contrast, no defects in the intracellular viral receptors of the RigI helicase family have been described to date. Defects in the PRRs show a broad variation in severity, have a narrow specificity for certain classes of pathogens, and often decrease in severity with age; these characteristics distinguish them from other forms of PIDs. Their discovery has led to important insights into the pathophysiology of infections, and may offer potential novel therapeutic targets for immunotherapy.

Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants.

The innate immune system plays an essential role in the host's first line of defense against microbial invasion, and involves the recognition of distinct pathogen-associated molecular patterns by pattern recognition receptors (PRRs). Activation of PRRs triggers cell signaling leading to the production of proinflammatory cytokines, chemokines and Type 1 interferons, and the induction of antimicrobial and inflammatory responses. These innate responses are also responsible for instructing the development of an appropriate pathogen-specific adaptive immune response. In this review, the focus is on different classes of PRRs that have been identified, including Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and the retinoic acid-inducible gene-I-like receptors, and their importance in host defense against infection. The role of PRR cooperation in generating optimal immune responses required for protective immunity and the potential of targeting PRRs in the development of a new generation of vaccine adjuvants is also discussed.

[The role of pattern-recognizing receptors in anti-infectious immunity].

Pattern-recognizing receptors (PRR) play a key role in the functioning of human immune system. They are the primary sensors of infection capable of distinguishing between various highly conservative molecular patterns (pathogen-associated molecular patterns (PAMPs)) contained in pathogenic organisms. Binding of these molecular patterns to PRR induces a variety of reactions of innate (secretion of proinflammatory cytokines and antimicrobial peptides, activation of phagocytosis, etc.) and adaptive (antibody processing and presentation, polarization of T-cell response, etc.) immunity. Great interest in the molecular mechanisms of pathogen recognition resulted in the discovery of numerous PRR. The aim of this review is to systematize the currently available data on PRR, their specificity, and role in the formation of anti-inflammatory immunity.

Gene polymorphisms of Toll-like and related recognition receptors in relation to the vaginal carriage of Gardnerella vaginalis and Atopobium vaginae.

Host genetic factors have previously been found to act as determinants of differential susceptibility to major infectious diseases. It is less clear whether such polymorphisms may also impose on pathogen recognition in mucosal overgrowth conditions such as bacterial vaginosis, an anaerobic overgrowth condition characterised by the presence of a vaginal biofilm consisting of the Gram-positive anaerobes Gardnerella vaginalis and Atopobium vaginae. We selected 34 single nucleotide polymorphisms pertaining to 9 genes involved with Toll-like receptor-mediated pathogen recognition and/or regulation (LBP, CD14, TLR1, TLR2, TLR4, TLR6, MD2, CARD15 and SIGIRR) and assessed in a nested case-control study their putative association with bacterial vaginosis, as diagnosed by Gram staining, and with the vaginal carriage of A. vaginae and G. vaginalis, as determined by species-specific PCR, among 144 pregnant women. Carriage of G. vaginalis during early pregnancy was associated with the -1155A>G substitution in the promoter region of the MD2 gene (p=0.041). The presence of A. vaginae during the first half of the pregnancy was significantly associated with the CD14 intron 2 1342G>T (p=0.039), the TLR1 exon 4 743A>G (p=0.038), and the CARD15 exon 4 14772A>T (p=0.012) polymorphisms, and marginally significantly associated with the LBP exon13 26842C>T (p=0.056), the CD14 promoter -260C>T (p=0.052), and the TLR1 promoter -7202A>G (p=0.062) polymorphisms. However, no association between gene polymorphisms and bacterial vaginosis as such could be documented. Our data suggest that some degree of genetic susceptibility involving pathogen recognition may occur with the key bacterial vaginosis organism, A. vaginae.

How pattern recognition receptor triggering influences T cell responses: a new look into the system.

Signaling through pattern recognition receptors (PRRs) in antigen-presenting cells (APCs) is required for the induction of T cell responses. PRR triggering in APCs induces important cellular modifications that have profound effects on antigen internalization, processing, MHC loading and antigen presentation. Accumulating experimental evidence also suggests that the fate of T cell responses depends strongly on the type of PRR triggered and the timing of PRR signaling. Here, we discuss the beneficial effects of PRR stimulation in the context of priming naive T cells, the generation and maintenance of effector/memory T cells, and the induction or break of tolerance. We propose a new classification into opsonic, phagocytic and instructive PRRs based on the functional properties of the receptors.

Innate sensors of microbial infection.

The innate immune system utilizes multiple families of pattern-recognition receptors (PRRs) to protect the host from infection. Each of these families contributes certain elements to the complement of innate effector functions that is elicited during an infection. Here we review the families of PRRs and explore examples of their cooperativity.