SEARCH · PubMed Health

Results for “pathogen effectors”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources

PubMed2005

Genome-wide analysis of host responses to the Pseudomonas aeruginosa type III secretion system yields synergistic effects.

The type III secretion system (TTSS) is a dedicated bacterial pathogen protein targeting system that directly affects host cell signalling and response pathways. Our goal was to identify host responses to the Pseudomonas aeruginosa effectors, introduced into target cells utilizing the TTSS. We carried out expression profiling of a human lung pneumocyte cell line A549 exposed to isogenic mutants of P. aeruginosa PAK lacking individual or a combination of TTSS components. We then devised a data analysis method to isolate the key responses to specific secreted bacterial effector proteins as well as components of the TTSS machinery. Individually, the effector proteins elicited host responses consistent with their known functions, many of which were cell cycle-related. However, our analysis has shown that the effector proteins elicit a distinct host transcriptional response when present in combination, suggesting a synergistic effect. Furthermore, the pattern of host transcriptional responses is consistent with the pore forming ability of the TTSS needle complex. This study shows that the individual components of the TTSS define an integrated system and that a systems biology approach is required to fully understand the complex interplay between pathogen and host.

Bacterial Proteins↗

PubMed1985

Complement effector mechanisms in health and disease.

Complement is an effector system able to mediate a number of biological activities in vitro and in vivo. Most familiar is the ability of the system to mediate the lytic destruction of numerous kinds of cells and pathogenic organisms including bacteria, viruses, and virus-infected cells. In addition, the complement system also activates neutrophils, monocytes, basophils, mast cells, and lymphocytes to perform specialized functions. While generally considered to be confined to the effector side of immune reactions, recent evidence indicates that the complement system also directly recognizes and is triggered by a number of bacteria and viruses as well as virus-infected cells in the absence of antibody. In such reactions, complement fulfills the recognition role normally associated with the antibody molecule or immune lymphocyte. The complement system may thus also function as a natural surveillance system operative prior to the induction of specific immunity. Involvement of the complement system in biological reactions has been ascertained by several techniques over the years. These include quantitation of individual complement components in human sera and demonstration of complement deposition in diseased tissues in human diseases and in experimental diseases in animals. Such techniques, however, have limitations in specificity and sensitivity. Assays which detect specific features of the complement activation process have become available in recent years. These tests detect the physical, chemical, or antigenic changes characteristic of the complement activation process. These assays are extremely specific and quantitative; furthermore, most are usable with samples from patients. Three general approaches have been utilized to develop such specific quantitative assays for complement activation. The first includes assays which quantitate activation-specific limited proteolysis of the complement components. The second type of assay includes tests which detect and quantitate new antigens or other activation-specific antigenic changes. The third category is represented by assays which detect and quantitate the protein-protein complexes characteristic of the activation process. Examples of tests presenting each of these approaches are given.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2026

Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective.

Host defense peptides (HDPs) are important components of the innate immune system that are used to combat pathogens and often rely on binding trace nutrient metals for their function. However, controlling nutrient metals may have other roles in host-symbiont interactions beyond poisoning harmful pathogens. This study characterizes the evolution, structural properties, and biochemical activity of the novel hymenopteran HDP abaecin-2. In myrmicine ants such as the fungus-growing tribe Attini, abaecin-2 has evolved to include an Amino-Terminal Cu(ii) and Ni(ii)-binding (ATCUN) motif, which we hypothesize binds copper, a trace nutrient that is enriched in attine ant colonies. Combined results from mass spectrometry, competitive binding assays, circular dichroism, and NMR indicate that the abaecin-2 peptide lacks a defined secondary structure and can associate with up to 2 Cu(ii) ions, one strongly bound at the ATCUN motif and another weakly bound, likely at a conserved histidine residue. Despite its copper-binding activity, abaecin-2 alone does not exhibit antibacterial activity against Escherichia coli or Bacillus subtilis (models for bacteria that live in ant fungus gardens). However, it synergizes with a model pore-forming peptide cecropin A to inhibit the growth of E. coli, similar to the related peptide abaecin-1. The copper-binding activity conferred by the ATCUN motif also protects copper-sensitive E. coli from excess copper toxicity. The dual context-dependent inhibitory and protective roles for abaecin-2 indicate that this previously under-characterized HDP may be used by attine ants to regulate both harmful and beneficial symbionts.

Journal Article↗

PubMed2026

Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective.

Host defense peptides (HDPs) are important components of the innate immune system that are used to combat pathogens and often rely on metal binding for their function. However, controlling trace nutrients such as transition metals may have other roles in host-symbiont interactions beyond poisoning harmful pathogens. This study characterizes the evolution, structural properties, and biochemical activity of the novel hymenopteran HDP abaecin-2. In myrmicine ants such as the fungus-growing tribe Attini, abaecin-2 has evolved to include an Amino-Terminal Cu(II) and Ni(II)-binding (ATCUN) motif, which we hypothesize may bind copper, a trace nutrient that is enriched in attine ant colonies. Combined results from mass spectrometry, competitive binding assays, circular dichroism, and NMR indicate that the abaecin-2 peptide lacks a defined secondary structure and can associate with up to 2 Cu(II) ions, one strongly bound at the ATCUN motif and another weakly bound, likely at a conserved histidine residue. Despite its copper-binding activity, abaecin-2 alone does not exhibit antibacterial activity against Escherichia coli or Bacillus subtilis (models for bacteria that live in ant fungus gardens). However, it synergizes with a model pore-forming peptide cecropin A to inhibit the growth of E. coli, similar to the related peptide abaecin-1. The copper-binding activity conferred by the ATCUN motif also protects copper-sensitive E. coli from excess copper toxicity. The dual, context-dependent inhibitory and protective roles we propose for abaecin-2 indicate that this previously under-characterized HDP may be used by attine ants to regulate both harmful and beneficial symbionts.

Journal Article↗

PubMed2004

Cytoplasmic entry of Listeria monocytogenes enhances dendritic cell maturation and T cell differentiation and function.

Protective immunity to the intracellular bacterial pathogen, Listeria monocytogenes, is mediated by a vigorous T cell response. In particular, CD8(+) cytolytic T cells provide essential effector function in the clearance of bacterial infection. The cytoplasmic entry of Listeria facilitated by listeriolysin O is an essential feature not only of the bacteria's virulence, but of the ability of the bacteria to elicit protective immunity in the host. To determine how cytoplasmic entry of Listeria regulates the development of protective immunity, we examined the effects of this process on the maturation of murine dendritic cells (DC) and on their ability to prime naive CD8(+) T cell responses. Costimulatory molecules (CD40, CD80, and CD86) were induced by listerial infection only when the bacteria invaded the cytoplasm. In addition, the production of IL-12, IL-10, IL-6, and TNF-alpha was most efficiently triggered by cytosolic Listeria. Naive T cells primed by peptide-loaded DC infected with either wild-type or nonhemolytic mutant Listeria proliferated equivalently, but a much larger proportion of those primed by wild-type Listeria monocytogenes produced IFN-gamma. Costimulatory molecules induced by cytosolic entry regulated T cell proliferation and, as a result, the number of functional T cells generated. DC-produced cytokines (specifically IL-12 and IL-10) were the major factors determining the proportion of T cells producing IFN-gamma. These data highlight the requirement for listerial cytoplasmic invasion for the optimal priming of T cell cytokine production and attest to the importance of this event to the development of protective CTL responses to this pathogen.

Animals↗

PubMed2001

Cationic peptides: effectors in innate immunity and novel antimicrobials.

Cationic antimicrobial peptides are produced by all organisms, from plants and insects to human beings, as a major part of their immediately effective, non-specific defences against infections. With the increasing development of antibiotic resistance among key bacterial pathogens, there is an urgent need to discover novel classes of antibiotics. Therefore, cationic peptides are being developed through clinical trials as anti-infective agents. In addition to their ability to kill microbes, these peptides seem to have effector functions in innate immunity and can upregulate the expression of multiple genes in eukaryotic cells. One such function might involve the dampening of signalling by bacterial molecules such as lipopolysaccharide and lipoteichoic acid.

Amino Acid Sequence↗

PubMed2026

Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome associated with dysregulation of GPR37 trafficking.

The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Humans↗

PubMed1998

Post-transcriptional contribution of a cAMP-dependent pathway to the formation of alpha- and beta/gamma-secretases-derived products of beta APP maturation in human cells expressing wild-type and Swedish mutated beta APP.

BACKGROUND: The physiopathological maturation of the beta-amyloid precursor protein can be modulated by effectors targeting a protein kinase C-dependent pathway. These agents increase the recovery of APP alpha, the physiological alpha-secretase-derived product of beta APP processing, and concomittantly lower the production of the pathogenic beta/gamma-secretase-derived A beta fragment. METHODS: We set up stably transfected HEK293 cells expressing wild-type or Swedish mutated beta APP. By combined metabolic labeling and/or immunoprecipitation procedures, we assessed the effect of various cAMP effectors on the production of the beta APP maturation products A beta 40, A beta 42, APP alpha, and its C-terminal counterpart. RESULTS: We show here that the cAMP-dependent protein kinase (PKA) effectors, dibutyryl-cAMP (dBut-cAMP) and forskolin, but not the inactive analog dideoxyforskolin, enhance the secretion of APP alpha and the intracellular production of its C-terminal counterpart (p10) in stably transfected HEK293 cells. The above agonists also drastically increase both A beta 40 and A beta 42 secretions and intracellular A beta recovery. The same influence was observed with HEK293 cells overexpressing the Swedish mutated beta APP. We attempted to delineate the relative contribution of transcriptional and post-transcriptional events in the cAMP-mediated response. We show here that the dBut-cAMP and forskolin-induced increase of APP alpha and A beta s secretions is not prevented by the transcription inhibitor actinomycin D. CONCLUSION: Our data suggest a major contribution of post-transcriptional events in the cAMP-dependent effect on beta APP maturation. It appears likely that cAMP triggers the PKA-dependent phosphorylation of a protein involved in beta APP maturation and occurring upstream to alpha- and beta/gamma-secretase cleavages.

Amyloid Precursor Protein Secretases↗

PubMed2005

Formation of a novel surface structure encoded by Salmonella Pathogenicity Island 2.

The type III secretion system (T3SS) encoded by Salmonella Pathogenicity Island 2 (SPI2) is essential for virulence and intracellular proliferation of Salmonella enterica. We have previously identified SPI2-encoded proteins that are secreted and function as a translocon for the injection of effector proteins. Here, we describe the formation of a novel SPI2-dependent appendage structure in vitro as well as on the surface of bacteria that reside inside a vacuole of infected host cells. In contrast to the T3SS of other pathogens, the translocon encoded by SPI2 is only present singly or in few copies at one pole of the bacterial cell. Under in vitro conditions, appendages are composed of a filamentous needle-like structure with a diameter of 10 nm that was sheathed with secreted protein. The formation of the appendage in vitro is dependent on acidic media conditions. We analyzed SPI2-encoded appendages in infected cells and observed that acidic vacuolar pH was not required for induction of SPI2 gene expression, but was essential for the assembly of these structures and their function as translocon for delivery of effector proteins.

Animals↗

PubMed2002

Two msbB genes encoding maximal acylation of lipid A are required for invasive Shigella flexneri to mediate inflammatory rupture and destruction of the intestinal epithelium.

Shigella flexneri is a Gram-negative pathogen that invades and causes inflammatory destruction of the human colonic epithelium, thus leading to bloody diarrhea and dysentery. A type III secretion system that delivers effector proteins into target eukaryotic cells is largely responsible for cell and tissue invasion. However, the respective role of this invasive phenotype and of lipid A, the endotoxin of the Shigella LPS, in eliciting the inflammatory cascade that leads to rupture and destruction of the epithelial barrier, was unknown. We investigated whether genetic detoxification of lipid A would cause significant alteration in pathogenicity. We showed that S. flexneri has two functional msbB genes, one carried by the chromosome (msbB1) and the other by the virulence plasmid (msbB2), the products of which act in complement to produce full acyl-oxy-acylation of the myristate at the 3' position of the lipid A glucosamine disaccharide. A mutant in which both the msbB1 and msbB2 genes have been inactivated was impaired in its capacity to cause TNF-alpha production by human monocytes and to cause rupture and inflammatory destruction of the epithelial barrier in the rabbit ligated intestinal loop model of shigellosis, indicating that lipid A plays a significant role in aggravating inflammation that eventually destroys the intestinal barrier. In addition, neutralization of TNF-alpha during invasion by the wild-type strain strongly impaired its ability to cause rupture and inflammatory destruction of the epithelial lining, thus indicating that TNF-alpha is a major effector of epithelial destruction by Shigella.

Acylation↗

PubMed2006

GATA transcription factor required for immunity to bacterial and fungal pathogens.

In the past decade, Caenorhabditis elegans has been used to dissect several genetic pathways involved in immunity; however, little is known about transcription factors that regulate the expression of immune effectors. C. elegans does not appear to have a functional homolog of the key immune transcription factor NF-kappaB. Here we show that that the intestinal GATA transcription factor ELT-2 is required for both immunity to Salmonella enterica and expression of a C-type lectin gene, clec-67, which is expressed in the intestinal cells and is a good marker of S. enterica infection. We also found that ELT-2 is required for immunity to Pseudomonas aeruginosa, Enterococcus faecalis, and Cryptococcus neoformans. Lack of immune inhibition by DAF-2, which negatively regulates the FOXO transcription factor DAF-16, rescues the hypersusceptibility to pathogens phenotype of elt-2(RNAi) animals. Our results indicate that ELT-2 is part of a multi-pathogen defense pathway that regulates innate immunity independently of the DAF-2/DAF-16 signaling pathway.

Animals↗

PubMed1995

Unique order of the lymphocyte subset induction in the liver and intestine of mice during Listeria monocytogenes infection.

We investigated how NK cells, extrathymic T cells, and thymus-derived T cells are activated in mice during infection with an intracellular pathogen, Listeria (L.) monocytogenes. Although macrophages and granulocytes are known to be involved in the elimination of this pathogen in an early phase of infection, it was still controversial what type of lymphocytes are induced as effectors in subsequent phases. When mice were ip injected with 1 x 10(3) L. monocytogenes (a sublethal dose), a prominent increase in the number of mononuclear cells in the liver and spleen was induced. Phenotypic analysis revealed that serial induction of lymphocyte subsets, NK cells-->extrathymic T cells-->thymus-derived T cells, occurred in these organs. Extrathymic T cells were estimated to have intermediate CD3 and a high level of IL-2 receptor beta-chain on the surface (i.e., intermediate CD3 cells). These mice became free from infection after 2 weeks. In the case of oral administration, 1 x 10(3) L. monocytogenes increased the number of cells in the liver and the number of intraepithelial and lamina propria lymphocytes in the intestine. Phenotypic analysis also showed a sequential induction of lymphocyte subsets in the liver and the induction of extrathymic T cells in the intestine. Preelimination of intermediate TCR cells and NK cells by in vivo treatment with anti-LFA-1 mAb made mice susceptible to an ip injected sublethal dose of L. monocytogenes. These results reveal a unique order of lymphocyte induction during listerial infection and indicate that extrathymic T cells might be one of the important cells in achieving resistance against L. monocytogenes.

Animals↗

PubMed1992

Transepithelial transport and mucosal defence II: secretion of IgA.

In this second article on mucosal defence and transepithelial transport, Jean-Pierre Kraehenbuhl and Marian Neutra discuss the part played by a special class of antibody, polymeric IgA, in the protection of mucosal surfaces lining the digestive, respiratory and genital tracts, and the implications for mucosal vaccines. Polymeric IgA crosslinks luminal antigens or pathogens, thus preventing their interaction with epithelial cells. Following stimulation by antigen in the organized mucosal lymphoid tissue, effector B lymphocytes enter the circulation and migrate to distant mucosal or glandular sites, where they differentiate into polymeric-IgA-producing plasma cells. These antibodies reach the environment by transport across the epithelial cells of mucosal and glandular tissues.

Journal Article↗

PubMed1997

Role of natural killer cells in innate resistance to protozoan infections.

Natural killer cells are now recognized as major effectors of innate resistance to protozoan parasites. The principal mechanism by which they control the growth of these pathogens is indirect, involving cytokine production rather than cytolytic activity. Recent studies have identified a series of positive and negative signals provided by cytokines and cellular interactions which regulate protozoa-induced natural killer cell function.

Animals↗

PubMed1999

Nitric oxide as a signal in plants.

Molecular, genetic and biochemical studies have identified key players in the signaling pathways regulating growth and development, as well as defense responses in plants. Recently, nitric oxide (NO) - the versatile and powerful effector of animal redox-regulated signaling and immune responses - was shown to mediate plant defense responses against pathogens. Interestingly, several key components involved in NO-mediated signaling in animals also appear to be operative in plants.

Animals↗

PubMed2001

The role of As60A, a TGF-beta homolog, in Anopheles stephensi innate immunity and defense against Plasmodium infection.

We have examined the constitutive and induced expression of As60A in Anopheles stephensi females. As60A is expressed throughout the body of A. stephensi, including the midgut, fat body and developing eggs. We discovered that As60A is induced in the midgut and carcass of A. stephensi in response to Plasmodium infection. Induction of As60A correlates with periods of parasite motility and reproduction. Further, induction is dependent on the intensity of parasite infection: low numbers of parasites do not induce As60A expression. Thus, we conclude that As60A is a component of the A. stephensi immune response to Plasmodium infection. The involvement of a member of the transforming growth factor beta (TGF-beta) super family in the mosquito immune response is analogous to the involvement of TGF-beta1 in the mammalian immune response to Plasmodium. The modulation of As60A and A. stephensi nitric oxide synthase (AsNOS) expression in response to Plasmodium indicates that homologs of effector (NOS) and regulator (TGF-beta1) gene super families may defend evolutionarily diverse hosts against a shared pathogen.

Animals↗

PubMed1997

A novel protein that participates in nonself discrimination of malignant cells by homologous complement.

The human complement (C) system protects an individual against substances of nonself origin, including xenografts and microbial pathogens. Human cells express C-regulatory proteins, CD46 and CD55, thereby circumventing attack by C3, a major effector of C. Nevertheless, certain malignant cells, particularly those undergoing apoptotic stress, can activate homologous C, overcoming the regulatory actions of CD46 and/or CD55. The molecular mechanisms whereby malignant cells are tagged by homologous C3 remain largely unknown. We identified a novel gene product that converts human cells into targets for homologous complement. Only malignant cells and cell lines exposed to Fas or X-irradiation stimuli produced this protein, designated M161Ag, which was an unglycosylated 43-kDa protein. Analysis of cloned cDNAs indicated that this molecule was a secretory protein containing five amino acids encoded by TGA codons. Its functions were unique in that once secreted from the tumor cells, it bound back to the surface of these cells and activated homologous complement (C3) via the alternative pathway, allowing for C3 deposition on the membrane. This molecule may offer new insight into innate immunity; surveillance of tumor cells by complement is a common feature in the human immune system.

Amino Acid Sequence↗

PubMed2003

Measuring the frequency of mouse and human cytotoxic T cells by the Lysispot assay: independent regulation of cytokine secretion and short-term killing.

Antigen-specific T cells demonstrate several potent effector functions during immune responses. Direct killing of infected cells is crucial for clearing viruses and other intracellular pathogens, but it has been difficult to measure the frequency of cytolytic cells. We have now developed a single-cell assay to measure the number of cytotoxic cells in a population, using a herpes simplex virus amplicon vector to express Escherichia coli beta-galactosidase in mouse or human target cells, and an Elispot to detect release of beta-galactosidase from killed target cells. This antigen-specific, perforin-dependent Lysispot assay has been combined with a cytokine Elispot in a two-color assay to confirm that cytotoxicity and interferon-gamma secretion are regulated independently. The simultaneous enumeration of cytokine-secreting and cytotoxic cells should be invaluable for ex vivo analysis of immune responses during infection and autoimmunity.

Animals↗