Genome-wide identification of scavenger receptor family genes in Octopus sinensis and their immune response to PGN, poly I:C, and Vibrio parahaemolyticus.

A Spätzle-Processing Enzyme Required for Toll Signaling Activation in Drosophila Innate Immunity

The mortality of septic shock in the pediatric population has improved over the last 2 decades with better supportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shock have been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not well understood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which is important to pathogen containment. Elements of the innate immune system activate the adaptive immune system in an antigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequent infection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immune cells and are capable of responding to highly conserved components of pathogens called pathogen associated molecular patterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. These receptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomal plasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRs are present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 like receptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated in components of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, and carbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganisms such as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs and PAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment and amplification of the full repertoire of the immune response. There are developmental differences in the immune systems of infants and children compared to adults. The innate immune system matures much earlier than the adaptive immune response and as a result infants and young children may be more reliant on their innate immune system. For this reason it important to fully understand the key elements of the innate immune response including the many categories of PRRs and their cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targets for therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signaling pathways as well as the major classes of PAMPs that activate them.

Innate immunity is an ancient form of host defense that is shared by almost all multicellular organisms (1, 2). However, it is not a redundant defense mechanism, and recent evidence has shown that innate immunity not only provides a first line of antimicrobial host defense, but also has a profound impact on the establishment of adaptive immune responses (1, 3). Upon infection, microorganisms are first recognized by cells of the host innate immune system, such as phagocytic leukocytes, endothelial and mucosal epithelial cells, and professional antigen-presenting cells. Recognition of pathogens is primarily mediated by a set of germline-encoded molecules on innate immune cells that are referred to as pattern recognition receptors (PRRs) (3). Well characterized PRRs include CD14, β2-integrins (CD11/CD18), C-type lectins, macrophage scavenger receptors, and complement receptors (CR1/CD35, CR2/CD21) (3). These PRRs are expressed as either membrane-bound or soluble proteins that recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are shared by many pathogens but not expressed by hosts (3). Examples of PAMPs include LPS, bacterial lipoprotein (BLP), peptidoglycan (PGN) lipoteichoic acid (LTA), unmethylated CpG DNA of bacteria, lipoarabinomannan (LAM) of mycobacteria, and mannans of yeast (3). Recognition of PAMPs by PRRs results in the activation of different intracellular signaling cascades that in turn lead to the expression of various effector molecules (3). One group of effector molecules consists of reactive oxygen and nitrogen intermediates and various antimicrobial peptides that have direct microbicidal activity and collectively provide immediate protection for hosts. Another group includes cytokines, chemokines, adhesion molecules, and acute phase proteins that are involved in inflammation and early host defense as well as the development of adaptive immune responses. The third group consists of the costimulatory molecules B7.1 and B7.2, which bind CD28 on T cells and act as the second signal for T-cell activation. Therefore, signaling by the PRRs helps to bridge innate and adaptive immunity and allows the host to cope more efficiently with microbial infection. In keeping with the important role that innate immunity plays in protecting multicellular organisms from infection, components of the innate immune response, including pathogen recognition molecules, signal transduction pathways, and downstream effector molecules, are all evolutionarily conserved and are used by insects, plants, and mammals (2). Recent studies on the recognition of microbial PAMPs have highlighted the critical role of one group of PRRs, the Toll-like receptors (TLRs), in pathogen recognition and host defense. These TLRs are distinguished from other PRRs by their ability to recognize and, more significantly, discriminate between, different classes of pathogens (reviewed in refs. 4, 5). Engagement of TLRs by pathogens leads to the activation of innate immune responses (5), and a major signaling target of the TLRs is activation of the transcription factor NF-κB, a key regulator of immune and inflammatory responses (reviewed in refs. 6–8). Interestingly, TLR-mediated NF-κB activation is also an evolutionarily conserved event that occurs in phylogenetically distinct species ranging from insects to mammals (5, 9, 10). Here, we focus on the role of the conserved TLR/NF-κB signaling pathway in innate immunity, as well as its impact on adaptive immune responses.

BackgroundManila clam (Ruditapes philippinarum) is a worldwide commercially important marine bivalve species. In recent years, however, microbial diseases caused high economic losses and have received increasing attention. To understand the molecular basis of the immune response to pathogen-associated molecular patterns (PAMPs) in R. philippinarum, transcriptome libraries of clam hepatopancreas were constructed at 24 h post-injection with Lipopolysaccharide (LPS), peptidoglycan (PGN), and polyinosinic-polycytidylic acid (poly(I:C)) and phosphate-buffered saline (PBS) control by using RNA sequencing technology (RNA-seq).ResultsA total of 832, 839, and 188 differentially expressed genes (DEGs) were found in LPS, PGN, and poly(I:C) challenge group compared with PBS control, respectively. Several immune-related genes and pathways were activated in response to the different PAMPs, suggesting these genes and pathways might specifically participate in the immune response to pathogens. Besides, the analyses provided useful complementary data to compare different PAMPs challenges in vivo. Functional enrichment analysis of DEGs demonstrated that PAMPs responsive signal pathways were related to apoptosis, signal transduction, immune system, and signaling molecules and interaction. Several shared or specific DEGs response to different PAMPs were revealed in R. philippinarum, including pattern recognition receptors (PRRs), antimicrobial peptides (AMPs), interferon-induced proteins (IFI), and some other immune-related genes were found in the present work.ConclusionsThis is the first study employing high throughput transcriptomic sequencing to provide valuable genomic resources and investigate Manila clam response to different PAMPs through in vivo challenges with LPS, PGN, and poly(I:C). The results obtained here provide new insights to understanding the immune characteristics of R. philippinarum response to different PAMPs. This information is critical to elucidate the molecular basis of R. philippinarum response to different pathogens invasion, which potentially can be used to develop effective control strategies for different pathogens.

Macrophage apoptosis is an important feature of atherosclerotic plaque development. Research directed at understanding the functional consequences of macrophage death in atherosclerosis has revealed opposing roles for apoptosis in atherosclerotic plaque progression. In early lesions, macrophage apoptosis limits lesion cellularity and suppresses plaque progression. In advanced lesions, macrophages apoptosis promotes the development of the necrotic core, a key factor in rendering plaques vulnerable to disruption and in acute lumenal thrombosis. The first section of this review will examine the role of phagocytic clearance of apoptotic macrophages, a process known as efferocytosis, in the dichotomous roles of macrophage apoptosis in early vs. advanced lesions. The second section will focus on the molecular and cellular mechanisms that are thought to govern macrophage death during atherosclerosis. Of particular interest is the complex and coordinated role that the endoplasmic reticulum (ER) stress pathway and pattern recognition receptors (PRRs) may play in triggering macrophage apoptosis.

Innate immune defects in atopic dermatitis

The transcriptomic expression of pattern recognition receptors: Insight into molecular recognition of various invading pathogens in Oyster Crassostrea gigas

This paper presents a study of the flow of ice in wedge-shaped converging channels. Such flows are encountered in the relatively constricted waters of the Canadian Arctic Archipelago. Ridging, lead opening patterns, development of a highpressure area, and arch formation are some of the processes which take place during ice flow through converging channels. An idealized geometry and steady wind forcing were used in the testing. The results give ice cover velocity, distribution of stresses, ice thickness, area coverage and ridging. Some of the conditions leading to arch formation at the constricted exit of the channel are explored.

Lipid peroxidation is a common event in health and is greatly accelerated in pro-inflammatory settings such as hypercholesterolemia. Consequently, oxidation-specific epitopes are generated, which are pro-inflammatory and immunogenic, leading to both adaptive and innate responses. Because innate immune mechanisms use conserved germline pattern recognition receptors (PRRs) that are preformed and present at birth, it is not obvious why they should bind to such epitopes. In this review, we put forward the hypothesis that because oxidation-specific epitopes are ubiquitous in both health and disease, and because they in essence represent "danger signals," they constitute a class of pathogen-associated molecular patterns leading to the natural selection of multiple innate PRRs that target such epitopes. We suggest that apoptotic cells, and the blebs and microparticles released from such cells, which are rich in oxidation-specific epitopes and thus pro-inflammatory, constitute an endogenous set of selecting antigens. In turn, natural antibodies, scavenger receptors, and soluble innate proteins, such as pentraxins, all represent PRRs that target such epitopes. We discuss the evidence for this hypothesis and the consequences of such responses in health and disease, such as atherosclerosis.

Molecular characterization of an LRR-only protein gene in Pacific white shrimp Litopenaeus vannamei: Sequence feature, expression pattern, and protein activity

IFN-α Enhances Poly-IC Responses in Human Keratinocytes by Inducing Expression of Cytosolic Innate RNA Receptors: Relevance for Psoriasis

Plant innate immunity is a potential basal defense system existing in plant kingdom. This system provides powerful weapons to the host plants to fight against viral, bacterial, fungal, and oomycete pathogens and serves as a surveillance system against invasion of pathogens. It is not active in normal healthy plants and it requires specific signals to get activated. Pathogen-associated molecular patterns (PAMPs) act as alarm/danger signals to trigger the plant innate immune responses. When pathogens land on the plant’s surface, plants read the molecular fingerprints/signatures of pathogens (PAMPs) by binding the PAMPs with cognate pattern-recognition receptors (PRRs) residing in plant cell plasma membrane and trigger several defense signaling systems. Pathogens contain a wide array of PAMPs of diverse chemical structures and every pathogen contains or secretes multiple PAMPs. Each PAMP may regulate induction of different defense genes. The time of induction, intensity of induction, and duration of induction of the defense signals may vary depending on PAMPs. Amount of PAMP available in the plant-pathogen interaction site may determine the intensity of induced gene expression. Each PAMP may regulate distinctly different signaling pathway(s). Sometimes different PAMPs may induce the same signaling system, but the intensity of the defense signaling gene expression may differ. The same PAMP may behave differently in different plant system. A single PAMP may not be able to activate all the defense signaling-related genes and several PAMPs may be required to activate the complex signaling systems. PAMPs may act synergistically or antagonistically in inducing defense signaling. Some PAMPs have additive effect, while others show antagonistic effect between them. The PAMPs are perceived as danger signals by PRRs and the PAMP-PRR complex activates the plant innate immunity. PAMPs trigger phosphorylation of PRRs. Fine control of membrane-resident PRR activity is essentially achieved by a combination of proper endoplasmic reticulum (ER) folding, degradation and trafficking of PRRs. Strict elimination of the misfolded PRR occurs in the absence of the identified ER folding machineries, which would avoid precocious immune activation. Pre-recognition membrane traffic of PRRs from the ER to their functional sites, together with post-recognition internalization is crucial for PRR function. The signals generated by PAMPs are perceived by PRRs and several second messengers are involved in transmission of the signals downstream of the PRRs. Highly complex networks of signaling pathways are activated by the PAMP-PRR signaling system.KeywordsInnate immunityPAMPsPRRsPAMP-PRR signaling complex • Second messengers • Trafficking of PRRs

N-Glycans attached to the ectodomains of plasma membrane pattern recognition receptors constitute likely initial contact sites between plant cells and invading pathogens. To assess the role of N-glycans in receptor-mediated immune responses, we investigated the functionality of Arabidopsis receptor kinases EFR and FLS2, sensing bacterial translation elongation factor Tu (elf18) and flagellin (flg22), respectively, in N-glycosylation mutants. As revealed by binding and responses to elf18 or flg22, both receptors tolerated immature N-glycans induced by mutations in various Golgi modification steps. EFR was specifically impaired by loss-of-function mutations in STT3A, a subunit of the endoplasmic reticulum resident oligosaccharyltransferase complex. FLS2 tolerated mild underglycosylation occurring in stt3a but was sensitive to severe underglycosylation induced by tunicamycin treatment. EFR accumulation was significantly reduced when synthesized without N-glycans but to lesser extent when underglycosylated in stt3a or mutated in single amino acid positions. Interestingly, EFR(N143Q) lacking a single conserved N-glycosylation site from the EFR ectodomain accumulated to reduced levels and lost the ability to bind its ligand and to mediate elf18-elicited oxidative burst. However, EFR-YFP protein localization and peptide:N-glycosidase F digestion assays support that both EFR produced in stt3a and EFR(N143Q) in wild type cells correctly targeted to the plasma membrane via the Golgi apparatus. These results indicate that a single N-glycan plays a critical role for receptor abundance and ligand recognition during plant-pathogen interactions at the cell surface.

C-type lectin response to bacterial infection and ammonia nitrogen stress in tiger shrimp (Penaeus monodon)

Melanin synthesis is essential for defense and development but must be tightly controlled because systemic hyperactivation of the prophenoloxidase and excessive melanin synthesis are deleterious to the hosts. The melanization cascade of the arthropods can be activated by bacterial lysine-peptidoglycan (PGN), diaminopimelic acid (DAP)-PGN, or fungal beta-1,3-glucan. The molecular mechanism of how DAP- or Lys-PGN induces melanin synthesis and which molecules are involved in distinguishing these PGNs are not known. The identification of PGN derivatives that can work as inhibitors of the melanization cascade and the characterization of PGN recognition molecules will provide important information to clarify how the melanization is regulated and controlled. Here, we report that a novel synthetic Lys-PGN fragment ((GlcNAc-MurNAc-L-Ala-D-isoGln-L-Lys-D-Ala)2, T-4P2) functions as a competitive inhibitor of the natural PGN-induced melanization reaction. By using a T-4P2-coupled column, we purified the Tenebrio molitor PGN recognition protein (Tm-PGRP) without causing activation of the prophenoloxidase. The purified Tm-PGRP recognized both Lys- and DAP-PGN. In vitro reconstitution experiments showed that Tm-PGRP functions as a common recognition molecule of Lys- and DAP-PGN-dependent melanization cascades.