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Results for “Innate Immunity Recognition”

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PubMed2005

Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults.

OBJECTIVE: To test for the association of single nucleotide polymorphisms of the innate immunity receptors cluster of differentiation (CD)-14, mannose-binding lectin, and Toll-like receptor-2 with clinical phenotype in critically ill patients with systemic inflammatory response syndrome. DESIGN: Genetic association study. SETTING: Tertiary care mixed medical-surgery intensive care unit at St. Paul's Hospital, Vancouver, BC, a teaching hospital associated with the University of British Columbia. PATIENTS: A cohort of 252 critically ill Caucasians with systemic inflammatory response syndrome. INTERVENTIONS: DNA was extracted from discarded blood. Clinical data were gathered by retrospective chart review. MEASUREMENTS AND MAIN RESULTS: C-159T CD14, the X/Y and B, C, and D polymorphisms of mannose-binding lectin, and T-16933A Toll-like receptor-2 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. We tested for association of genotype with prevalence of positive bacterial cultures, type of organism (Gram-positive, Gram-negative, other), sepsis and septic shock at admission to the intensive care unit, and 28-day survival. CD14 -159TT was associated with increased prevalence of positive bacterial cultures and with Gram-negative bacteria. Mannose-binding lectin haplotype pairs XO/O and O/O were also associated with increased prevalence of positive bacterial cultures but not with a specific organism class. Toll-like receptor-2 -16933AA was associated with increased prevalence of sepsis and with Gram-positive bacteria. In contrast, the polymorphisms were not associated with increased prevalence of septic shock or altered 28-day survival. CONCLUSIONS: Single nucleotide polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of positive bacterial cultures and sepsis but not with altered prevalence of septic shock or decreased 28-day survival. Furthermore, CD14 single nucleotide polymorphisms were associated with Gram-negative bacteria and Toll-like receptor-2 with Gram-positive bacteria, whereas mannose-binding lectin was not associated with a particular organism class. Thus, single nucleotide polymorphisms in innate immunity receptors may alter recognition and clearance of bacteria without changing outcomes of critically ill adults with systemic inflammatory response syndrome.

Adult↗

PubMed2000

DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA.

Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleotides (ISS-ODN) stimulate innate immunity. However, the molecular recognition mechanism that initiates signaling in response to bacterial DNA and ISS-ODN has not been identified. Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12. Further analysis using BMDM of IKKbeta(-/-) revealed that both DNA-PKcs and IKKbeta are essential for normal cytokine production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-kappaB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.

Androstadienes↗

PubMed2003

Molecular approaches to disease control.

Recent advances in molecular biology, genomics, and immunology are revolutionizing our approach to managing infectious diseases of humans, livestock, and poultry. One of the most interesting additions to the armamentarium of research focusing on controlling infectious diseases has been a better understanding of how the host's innate immune system recognizes "danger" signals. Additionally, there has been recognition of the relationship between the innate and the specific arms of the immune system. For example, the recent discovery that CpG motifs can modulate immune responses has been used both as an adjuvant to enhance the responses to vaccines, as well as a direct immunostimulant to prevent infections. Using an Escherichia coli chicken model, we have been able to prevent cellulitis in chickens with CpG alone. Thus, CpG can be used immunoprophylactically to reduce infectious diseases. In addition, we will describe how CpG formulations with various antigens; recombinant proteins, peptides, and conventional vaccines can enhance immune responses to each of these different vaccine combinations. What is even more interesting is that CpG incorporation in vaccines can shift the immune response from a predominant T helper 2 (Th2)-like immune response generally induced by killed or subunit proteins to a much more balanced Th1-Th2 response. These immunomodulatory effects have significant implications for management of infectious diseases of all vertebrates.

Animals↗

PubMed2006

ENU-mutagenesis: insight into immune function and pathology.

In random chemical mutagenesis, gene discovery is driven by phenotypes rather than by hypotheses. A standard dose of N-ethyl-N-nitrosourea results in approximately 30 coding mutations in male G1 mice, of which approximately 4 can be propagated to homozygosity in 3 generations. In recent years, large-scale screens of such G3 mice for phenotypes of interest to immunologists have revealed clues to the number of genes responsible for key immune responses, such as innate recognition of pathogens and autoantibody production. More than 20 of the phenotypes that exhibit a simple (Mendelian) pattern of inheritance have been mapped. Novel alleles have revealed new pathways of host defense, allergy and autoimmunity.

Alleles↗

PubMed2004

Analysis of signal-dependent changes in the proteome of Drosophila blood cells during an immune response.

Innate immunity is based on the recognition of cell-surface molecules of infecting agents. Microbial substances, such as peptidoglycan, lipopolysaccharide, and beta-1,3-glucans, produce functional responses in Drosophila hemocytes that contribute to innate immunity. We have used two-dimensional gel electrophoresis and MS to resolve lipopolysaccharide-induced changes in the protein profile of a Drosophila hemocytic cell line. We identified 24 intracellular proteins that were up- or down-regulated, or modified, in response to immune challenge. Several proteins with predicted immune functions, including lysosomal proteases, actin-binding/remodeling proteins, as well as proteins involved in cellular responses to oxidative stress, were affected by the immune assault. Intriguingly, a number of the proteins identified in this study have recently been implicated in phagocytosis in higher vertebrates. We suggest that phagocytosis is activated in Drosophila hemocytes by the presence of microbial substances, and that this activation constitutes an evolutionarily conserved arm of innate immunity. In addition, a number of proteins involved in calcium-regulated signaling, mRNA processing, and nuclear transport were affected, consistent with a possible role in reprogramming of gene expression. In conclusion, the present proteome analysis identified many proteins previously not linked to innate immunity, demonstrating that differential protein profiling of Drosophila hemocytes is a valuable tool for identification of new players in immune-related cellular processes.

Animals↗

PubMed2005

CD4+-T-cell responses generated during murine Salmonella enterica serovar Typhimurium infection are directed towards multiple epitopes within the natural antigen FliC.

The flagellar filament protein FliC is a natural antigen recognized by memory CD4+ T cells recovered from Salmonella enterica serovar Typhimurium-infected humans and mice. To further investigate T-cell responses to FliC, we derived FliC-specific CD4+-T-cell clones from mice of two different haplotypes following oral S. enterica serovar Typhimurium infection. Using C-terminal truncations of MalE-FliC recombinant fusion proteins, we mapped antigenic activity to four different regions of FliC; three of the four epitope-containing regions were present in both FliC and the alternate flagellin subunit FljB. We determined that two novel FliC epitopes were also present in flagellins from several gram-negative enteric bacterial species: E(k)-restricted FliC 80-94 (amino acids 80 to 94) and A(b)-restricted FliC 455-469. Further mapping confirmed the presence of two previously identified FliC epitopes: A(k)-restricted FliC 339-350 and A(b)-restricted FliC 428-442. Therefore, like the recognition site of the innate immune receptor Toll-like receptor 5, three of four FliC epitopes recognized by CD4+ T cells colocalize in the D0/D1 domains of FliC. Salmonella-infected macrophages and dendritic cells stimulated epitope-specific CD4+-T-cell proliferation; infected dendritic cells also activated T cells to produce gamma interferon. These data demonstrate that Salmonella infection generates murine CD4+-T-cell responses to multiple epitopes in the natural antigen FliC and that recognition of infected phagocytes by FliC-specific CD4+ T cells triggers effector functions known to be essential for protective immunity. Together, these data suggest that FliC-specific CD4+ T cells may contribute to cell-mediated host defenses against Salmonella.

Amino Acid Sequence↗

PubMed2005

Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection.

Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, -0.76; range, -2.85 to +0.21 log(10) units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2'-, 5'- oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects.

Antiviral Agents↗

PubMedDate not supplied

Innate immune response to intramammary infection with Serratia marcescens and Streptococcus uberis.

Streptococcus uberis and Serratia marcescens are Gram-positive and Gram-negative bacteria, respectively, that induce clinical mastitis. Once initial host barrier systems have been breached by these pathogens, the innate immune system provides the next level of defense against these infectious agents. The innate immune response is characterized by the induction of pro-inflammatory cytokines, as well as increases in other accessory proteins that facilitate host recognition and elimination of the pathogens. The objective of the current study was to characterize the innate immune response during clinical mastitis elicited by these two important, yet less well-studied, Gram-positive and Gram-negative organisms. The pro-inflammatory cytokine response and changes in the levels of the innate immune accessory recognition proteins, soluble CD14 (sCD14) and lipopolysaccharide (LPS)-binding protein (LBP), were studied. Decreased milk output, induction of a febrile response, and increased acute phase synthesis of LBP were all characteristic of the systemic response to intramammary infection with either organism. Infection with either bacteria similarly resulted in increased milk levels of IL-1 beta, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, sCD14, LBP, and the complement component, C5a. However, the duration of and/or maximal changes in the increased levels of these inflammatory markers were significantly different for several of the inflammatory parameters assayed. In particular, S. uberis infection was characterized by the sustained elevation of higher milk levels of IL-1 beta, IL-10, IL-12, IFN-gamma, and C5a, relative to S. marcescens infection. Together, these data demonstrate the variability of the innate immune response to two distinct mastitis pathogens.

Acute-Phase Proteins↗

PubMed2004

Structural basis for peptidoglycan binding by peptidoglycan recognition proteins.

Peptidoglycan (PGN) recognition proteins (PGRPs) are pattern-recognition receptors of the innate immune system that bind and, in some cases, hydrolyze bacterial PGNs. We determined the crystal structure, at 2.30-A resolution, of the C-terminal PGN-binding domain of human PGRP-Ialpha in complex with a muramyl tripeptide representing the core of lysine-type PGNs from Gram-positive bacteria. The peptide stem of the ligand is buried at the deep end of a long binding groove, with N-acetylmuramic acid situated in the middle of the groove, whose shallow end can accommodate a linked N-acetylglucosamine. Although most interactions are with the peptide, the glycan moiety also seems to be essential for specific recognition by PGRPs. Conservation of key PGN-contacting residues shows that all PGRPs employ this basic PGN-binding mode. The structure pinpoints variable residues that likely mediate discrimination between lysine- and diaminopimelic acid-type PGNs. We also propose a mechanism for PGN hydrolysis by Zn(2+)-containing PGRPs.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Interferons (IFNs) are key cytokines in both innate and adaptive antiviral immune responses--and viruses counteract IFN action.

Interferons (IFNs) are transcriptionally regulated cytokines and key players in the innate antiviral immune response. Upon recognition of a virus, or its molecular patterns, by the Toll-like receptors of dendritic cells (DCs), high levels of IFNs are expressed by these cells. This in turn stimulates DC maturation and the subsequent expression of proinflammatory cytokines and costimulatory molecules, leading to the transition to an adaptive antiviral immunity. Conversely, viruses have developed diverse strategies to counterattack host defenses in order to generate their progenies.

Animals↗

PubMed2001

C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.

Removal of apoptotic cells is essential for maintenance of tissue homeostasis, organogenesis, remodeling, development, and maintenance of the immune system, protection against neoplasia, and resolution of inflammation. The mechanisms of this removal involve recognition of the apoptotic cell surface and initiation of phagocytic uptake into a variety of cell types. Here we provide evidence that C1q and mannose binding lectin (MBL), a member of the collectin family of proteins, bind to apoptotic cells and stimulate ingestion of these by ligation on the phagocyte surface of the multifunctional protein, calreticulin (also known as the cC1qR), which in turn is bound to the endocytic receptor protein CD91, also known as the alpha-2-macroglobulin receptor. Use of these proteins provides another example of apoptotic cell clearance mediated by pattern recognition molecules of the innate immune system. Ingestion of the apoptotic cells through calreticulin/CD91 stimulation is further shown to involve the process of macropinocytosis, implicated as a primitive and relatively nonselective uptake mechanism for C1q- and MBL-enhanced engulfment of whole, intact apoptotic cells, as well as cell debris and foreign organisms to which these molecules may bind.

Apoptosis↗

PubMed2001

Innate immunity and its evasion and suppression by hymenopteran endoparasitoids.

Recent studies suggest that insects use pattern recognition molecules to distinguish prokaryotic pathogens and fungi from "self" structures. Less understood is how the innate immune system of insects recognizes endoparasitic Hymenoptera and other eukaryotic invaders as foreign. Here we discuss candidate recognition factors and the strategies used by parasitoids to overcome host defense responses. We suggest that host-parasitoid systems are important experimental models for studying how the innate immune system of insects recognizes foreign invaders that are phylogenetically more closely related to their hosts. The strategies used by parasitoids suggest that insects may employ "hidden-self" recognition molecules for attacking foreign objects intruding the open circulatory system. BioEssays 23:344-351, 2001.

Animals↗

PubMed1999

A pattern recognition protein for peptidoglycan. Cloning the cDNA and the gene of the silkworm, Bombyx mori.

Peptidoglycan recognition protein (PGRP) specifically binds to peptidoglycan and is considered to be one of the pattern recognition proteins in the innate immunity of insect. The PGRP is an essential component for peptidoglycan to trigger the prophenoloxidase cascade that is now recognized to be an important insect defense mechanism. We cloned cDNA encoding PGRP from the silkworm fat body cDNA library. Northern blot analysis showed that the PGRP gene is constitutively expressed in the fat body, epithelial cell, and hemocytes of naive silkworms. Furthermore, a bacterial challenge intensified the gene expression, with the maximal period being from 6 to 36 h after infection. The upstream sequence of the cloned PGRP gene was shown to contain putative cis-regulatory elements similar to the NF-kappaB-like element, interferon-response half-element, and GATA motif element, which have been found in the promoters of the acute phase protein genes of mammals and insects. A homology search revealed that the homologs of silkworm PGRP are present in mice, nematodes, and bacteriophages. This suggests that the recognition of peptidoglycan as foreign is effected in both vertebrates and invertebrates by PGRP homologs with an evolutionally common origin.

Amino Acid Sequence↗

PubMed2005

SLE: challenges and candidates in human disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immunological hyperactivity and multi-system organ damage. A complex genetic trait involving multiple genes, with both genetic heterogeneity and a threshold effect for disease expression, SLE involves abnormalities of both the innate and adaptive immune systems. Recognition of an 'interferon signature' in SLE leukocytes, of the role of B cells in promoting disease activity, and of FCGR3A alleles as a biomarker of end organ damage, provide important insights into disease pathogenesis. Nonetheless, coordinated studies in humans and model systems hold promise for an even more rapid advance in understanding pathways of disease development and strategies for intervention. More effective markers of disease risk, disease activity, severity of organ damage and outcomes would facilitate earlier diagnosis and guide appropriately targeted treatment.

B-Lymphocytes↗

PubMed2005

Mannose-binding lectin in chronic hepatitis B virus infection.

Mannose binding lectin (MBL) is a pattern-recognition molecule of the innate immune system. The roles of MBL and its gene (mbl2) polymorphisms, -221X/Y and codon 54A/B, in hepatitis B virus (HBV) infection were investigated in this study. We recruited 320 nonprogressed hepatitis B surface antigen (HBsAg) carriers; 199 progressed HBsAg carriers with hepatocellular carcinoma or cirrhosis; 87 spontaneously recovered individuals who were HBsAg negative and anti-HBs and anti HBc positive; and 484 controls who were naïve to HBV. There was no significant difference between nonprogressed carriers, spontaneously recovered individuals, and controls in terms of serum MBL levels and mbl2 polymorphisms distributions. However, the low MBL genotypes had a dose-dependent correlation with the cirrhosis and hepatocellular carcinoma in progressed carriers with odds ratios of 1.36 and 3.21 for the low and extremely low MBL genotypes, respectively (P = .01). The low-expression promoter haplotype XA (OR = 1.97) and the mutant haplotype YB (OR = 1.90) were also associated with the cirrhosis and hepatocellular carcinoma (P = .002). As expected, the lower serum MBL levels in progressed carriers as compared with nonprogressed carriers were due to an overrepresentation of low and extremely low MBL genotypes. Moreover, MBL could bind HBsAg in a dose- and calcium-dependent and mannan-inhibitable manner in vitro, suggesting that binding occurs via the carbohydrate recognition domains. This binding also enhanced C4 deposition. In conclusion, these results suggest that low MBL genotypes associate with the occurrence of cirrhosis and hepatocellular carcinoma in progressed HBsAg carriers, and MBL can bind HBsAg.

Adult↗

PubMed2006

Iron-withholding strategy in innate immunity.

The knowledge of how organisms fight infections has largely been built upon the ability of host innate immune molecules to recognize microbial determinants. Although of overwhelming importance, pathogen recognition is but only one of the facets of innate immunity. A primitive yet effective antimicrobial mechanism which operates by depriving microbial organisms of their nutrients has been brought into the forefront of innate immunity once again. Such a tactic is commonly referred to as the iron-withholding strategy of innate immunity. In this review, we introduce various vertebrate iron-binding proteins and their invertebrate homologues, so as to impress upon readers an obscured arm of innate immune defense. An excellent comprehension of the mechanics of innate immunity paves the way for the possibility that novel antimicrobial therapeutics may emerge one day to overcome the prevalent antibiotic resistance in bacteria.

Animals↗

PubMed2005

Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution.

Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors of the innate immune system that bind peptidoglycans (PGNs) of bacterial cell walls. These molecules, which are highly conserved from insects to mammals, contribute to host defense against infections by both Gram-positive and Gram-negative bacteria. Here, we present the crystal structure of human PGRP-S at 1.70A resolution. The overall structure of PGRP-S, which participates in intracellular killing of Gram-positive bacteria, is similar to that of other PGRPs, including Drosophila PGRP-LB and PGRP-SA and human PGRP-Ialpha. However, comparison with these PGRPs reveals important differences in both the PGN-binding site and a groove formed by the PGRP-specific segment on the opposite face of the molecule. This groove, which may constitute a binding site for effector or signaling proteins, is less hydrophobic and deeper in PGRP-S than in PGRP-IalphaC, whose PGRP-specific segments vary considerably in amino acid sequence. By docking a PGN ligand into the PGN-binding cleft of PGRP-S based on the known structure of a PGRP-Ialpha-PGN complex, we identified potential PGN-binding residues in PGRP-S. Differences in PGN-contacting residues and interactions suggest that, although PGRPs may engage PGNs in a similar mode, structural differences exist that likely regulate the affinity and fine specificity of PGN recognition.

Amino Acid Sequence↗

PubMed2005

Immunostimulatory oligonucleotides in therapy of allergic diseases.

At present, the improvement of hygienic life standards is considered as an environmental condition, increasing the prevalence of allergic diseases, as early contact with some pathogens is, according to the hygiene hypothesis, required for maturation of the immune system. The recognition of microbial components involves acquired and innate immunity mechanisms. Recently, the link between innate and acquired immunity has been discovered. It involves the evolutionarily old Toll-like receptor (TLR) system. Ligands recognised by TLRs include unmethylated deoxycytidil-deoxyguanosine (CpG) motif-containing microbial DNA. TLR-mediated signalling induces expression of cytokines preferentially promoting a Th1-directed response. Therefore, synthetic CpG motif-containing immunostimulatory oligonucleotides could be employed in causal allergy treatment. This review discusses some molecular aspects of the TLR system, as well as results of animal studies and early experiences, including treatment safety, from human clinical trials with immunostimulatory CpG motif-containing oligonucleotides.

Adjuvants, Immunologic↗