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 523 records · Page 29Linked to original sources

PubMed2003

Lymphocyte distribution in the tonsils prior to and after influenza vaccination.

The tonsils, consisting of the adenoid, tubal, palatine and pharyngeal tonsils, form a ring like structure in humans called Waldeyer's ring. The ring of tonsils is rich in lymphocytes and may play an important role as a reservoir of memory and immune competent cells serving the respiratory tract. The tonsils may also function as an activating and effector site for immune responses against respiratory pathogens. In this study, we have examined histological tissue sections from palatine tonsils for influenza specific antibody secreting cells (ASC) and several cell surface markers, from non-vaccinated and influenza vaccinated subjects. We found an increase in the number of influenza specific ASC in the tonsils of the influenza vaccinated subjects. These ASC was found scattered inside and surrounding the germinal centres, indicating that they may have homed to the tonsils. In addition, we observed a significant decrease in CD4 positive cells in tonsils of vaccinated subjects. Similar trends were also detected for CD45RA and CD45RO positive cells, which were significantly reduced in the vaccinated tonsils. The number of macrophages bearing the CD68 surface marker increased in numbers in vaccinated subjects. This shows that dynamic changes takes place in the tonsils after parenteral influenza vaccination, which may point to an important role of the tonsils in combating respiratory pathogens.

Adult↗

PubMed1997

Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB.

SETTING: Although nitric oxide (NO) is a major proximate mediator of microbicidal activity in murine macrophages against intracellular pathogens including mycobacteria, its production by and effector role in human macrophages is not clear. OBJECTIVE: To determine the capacity of Mycobacterium tuberculosis (MTB) to stimulate NO in human monocytes (MN) and alveolar macrophages (AM) and to assess the relationship between NO production and intracellular growth of MTB. DESIGN: NO production (measured as nitrite) by MTB (H37Ra)-infected macrophages and intracellular growth of MTB were measured in cells from 17 healthy subjects. RESULTS: MTB (5:1, MTB:cells) stimulated little to no NO by MN, but induced NO in AM at days 4 and 7 after infection. There was, however, variability in the response by AM to MTB: among seven subjects MTB-induced NO was low (4 +/- 2 microM, mean +/- SE); six subjects were moderate (56 +/- 11); four subjects were high (502 +/- 167). NO synthase inhibitors inhibited the production of NO by AM but did not significantly affect the intracellular growth of MTB, although a trend towards increased intracellular growth was seen on day 4 of culture. Intracellular growth of MTB in AM from low NO producers was significantly higher than that in AM from moderate NO producers, P < or = 0.05. Inducible NO synthase (iNOS) mRNA by RT-PCR was constitutively expressed by both MN and AM, but was further stimulated by MTB in AM > MN; MTB-induced iNOS protein was present in both MN and AM by Western blot analysis. CONCLUSION: Thus, MTB-infected human AM are capable of producing NO and NO production correlates with intracellular growth inhibition of MTB in AM suggesting that NO may serve either directly or indirectly as a mycobactericidal mediator in human tissue macrophages.

Adult↗

PubMed2002

Immune response to Salmonella: location, location, location?

Successful immunity against Salmonella infections is dependent on the generation of CD4(+) T helper cells and to a lesser extent on antibody production and CD8(+) T cells. The cells within the lymphatic tissue of the gut are likely to be central for the orchestration of a proper and rapid response. The anatomical restriction of the pathogen may also determine the distribution of effector cells. In this issue of Immunity, McSorley et al. address both of these processes using identifiable CD4 T cells that are specific for Salmonella typhimurium. Such cells localize to the Peyer's patches of the small intestine when the bacteria are delivered orally.

Animals↗

PubMed2006

Regulation of cytokine production during phagocytosis of apoptotic cells.

Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic cells would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The IL-12 family of cytokines (IL-12, IL-23, and IL-27) and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells (APCs) and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro- and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein (GC-BP), through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.

Animals↗

PubMed2002

Fcgamma receptor-mediated phagocytosis of Plasmodium falciparum-infected erythrocytes in vitro.

Although convincing evidence exists for the role of immunoglobulin G (IgG) antibodies in immunity to malaria, antibody titres do not usually predict protection. In this study we have assessed the interaction between Plasmodium falciparum-infected erythrocytes (PE), opsonized with immune serum containing different amounts of IgG antibody isotypes, with either THP-1 cells, ex-vivo human monocytes or IIAI.6 transfectant cells expressing Fc(gamma)RIIa-Arg/Arg131 or -His/His131 allotypes. Our results show that PMA-treated THP-1 cells were capable of phagocytosing serum-opsonized PE by Fc(gamma)RI (CD64) and Fc(gamma)RIIa (CD32), acting synergistically. The known Fc(gamma)RIIa polymorphism motivated us to examine its influence on IgG isotype-mediated phagocytosis of opsonized PE with human monocytes and the IIAI.6 transfectant cells expressing either allelic forms. Regardless of the cell type, PE phagocytosis with Fc(gamma)RIIa-His/His131 was highest following opsonization with a predominantly IgG3-containing immune serum pool. In contrast, PE phagocytosis with Fc(gamma)RIIa-Arg/Arg131 tended to be higher with an IgG1-containing pool. These results suggest a genetically determined influence of effector cell phenotype on IgG antibody-pathogen interaction in P. falciparum malaria.

Adolescent↗

PubMed2003

Genetic and molecular evidence that the Pseudomonas syringae type III effector protein AvrRpt2 is a cysteine protease.

Upon delivery to the plant cell during infection, the Pseudomonas syringae effector protein AvrRpt2 undergoes proteolytic processing, enhances pathogen virulence and causes the elimination of the Arabidopsis RIN4 protein. A structure-prediction method was employed in order to investigate possible biochemical functions of AvrRpt2. Results of a secondary structure prediction algorithm suggest that the functional C-terminal portion of AvrRpt2 is a cysteine protease. Mutation of predicted catalytic residues within this portion of AvrRpt2 abolished in planta processing, elimination of Arabidopsis RIN4, and the ability to trigger an RPS2-specific resistance response. These data indicate that AvrRpt2 is most likely a sequence divergent cysteine protease whose activity is required for elimination of RIN4 during infection.

Amino Acid Sequence↗

PubMed2000

The role of nitric oxide in the innate resistance to microfilariae of Litomosoides sigmodontis in mice.

Nitric oxide (NO) has been shown to be an important effector mechanism in the defence against various pathogens, including filariae. The production of NO, as well as H2O2, is induced by the Th1 cytokine IFN-gamma. Therefore, the microfilariae (mf) of filarial nematodes, which are known to elicit the release of IFN-gamma, may be a target of NO release. In this study, we found that mf of the filarial species Litomosoides sigmodontis were resistant to the attack of H2O2, but vulnerable to NO exposure in vitro by a chemical NO donor, as well as activated macrophages. Adult worms were considerably less affected by exposure to NO. In-vivo production of NO following injection of mf, in this and previous studies, suggested a central role in the defence to filariae. However, neither pharmaceutical inhibition of nitric oxide synthesis, nor genetic knockout of the gene for inducible nitric oxide synthase (iNOS), abrogated resistance to circulating mf in mice. Interestingly, however, iNOS-KO mice showed higher interleukin (IL)-2 responses and lower IL-10 production, compared to their wild-type counterparts. In conclusion, despite its effectiveness in vitro and the observed production of NO by ex vivo cells following infection, nitric oxide seems not to be an important factor in elimination of mf of L. sigmodontis in vivo. However, it may have a regulatory role in the immune response.

Animals↗

PubMed2006

Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling.

To overcome host defenses, bacterial pathogens of the genus Yersinia inject specific effector proteins into colonized mammalian cells. One such virulence factor, YopJ, inhibits the host inflammatory response and induces apoptosis of immune cells by blocking multiple signaling pathways, including the MAPK and NF-kappaB pathways. In this study, we show that YopJ exerts its deleterious effects by catalyzing the acetylation of two serine residues in the activation loop of the MAP kinase kinase, MEK2. This covalent modification prevents the phosphorylation of these serine residues that is required for activation of MEK2 and downstream signal propagation. We also show that YopJ causes acetylation of a threonine residue in the activation loop of both the alpha and beta subunits of the NF-kappaB pathway kinase, IKK. These results establish a hitherto uncharacterized mode of action for bacterial toxins and suggest the possibility that serine/threonine acetylation may occur even under nonpathogenic conditions and may be a widespread protein modification regulating protein function in eukaryotic cells.

Acetylation↗

PubMedDate not supplied

Basis and implications of selectively diminished cytokine production in neonatal susceptibility to infection.

The human neonate is unduly susceptible to infection with viruses and other pathogens, such as Toxoplasma and Listeria, that survive and replicate within cells. Cellular immunity is the major mechanism of host defense against these intracellular pathogens. Selective immaturity in certain functions of T lymphocytes appears to be a major factor in the neonate's susceptibility to these infections. Particularly striking is the deficiency in production of interferon-gamma. We review the data regarding the deficiency in the production of interferon-gamma by cells of healthy and infected neonates, discuss what is known regarding the cellular and molecular mechanisms for this deficiency, and review the unique role played by interferon-gamma in host defense against intracellular pathogens. The response of the neonate's effector cells to the immunoenhancing effects of interferon-gamma appears to be variable; diminished enhancement by interferon-gamma of cytotoxic cell function and the production of tumor necrosis factor by macrophages may further compound the effects of diminished production of interferon-gamma.

Disease Susceptibility↗

PubMed2003

SseG, a virulence protein that targets Salmonella to the Golgi network.

Intracellular replication of the bacterial pathogen Salmonella enterica occurs in membrane-bound compartments called Salmonella-containing vacuoles (SCVs). Maturation of the SCV has been shown to occur by selective interactions with the endocytic pathway. We show here that after invasion of epithelial cells and migration to a perinuclear location, the majority of SCVs become surrounded by membranes of the Golgi network. This process is dependent on the Salmonella pathogenicity island 2 type III secretion system effector SseG. In infected cells, SseG was associated with the SCV and peripheral punctate structures. Only bacterial cells closely associated with the Golgi network were able to multiply; furthermore, mutation of sseG or disruption of the Golgi network inhibited intracellular bacterial growth. When expressed in epithelial cells, SseG co-localized extensively with markers of the trans-Golgi network. We identify a Golgi-targeting domain within SseG, and other regions of the protein that are required for localization of bacteria to the Golgi network. Therefore, replication of Salmonella in epithelial cells is dependent on simultaneous and selective interactions with both endocytic and secretory pathways.

Amino Acid Sequence↗

PubMed2002

Revisiting the "hygiene hypothesis" in gastrointestinal allergy.

The "hygiene hypothesis" in its original form hypothesized that infection in early childhood acquired through unhygienic contact with siblings or the mother may prevent the development of allergic disease. Several recent epidemiologic surveys showing an inverse relationship between the frequency of infectious disease and the incidence of allergic diseases lend support to this hypothesis. Allergen sensitization of the immune system can occur early in utero against a background of neonatal commitment to a Th2 immune response involving the production of Th2 cytokines (eg, interleukin (IL)-4, IL-5, IL-13) that are the principal mediators of allergic inflammation. Continued allergen exposure is associated with predominantly CD4+ Th2 cell proliferation but does not exclude a minor Th1 allergen-specific subpopulation that can be further expanded nonspecifically and polyclonally by microbial superantigens or as bystanders, by interferon-gamma (IFN-gamma) and IL-2 released from Th1 effectors responding to antigens associated with infectious pathogens. Th1 cytokines can also subvert allergen-specific Th2 lymphocytes to become allergen-specific Th1 cells-a process reminiscent of the increased tendency of the maturing immune system of growing adults to mount a Th1 response to some environmental and dietary antigens. Unlike Th2 cytokines, IFN-gamma and IL-2 inhibit B-cell production of IgE and, hence, delimit the capacity of mast cells to degranulate and release allergenic mediators. The ability of infectious agents through their danger signals to initiate a Th1 response that deviates the Th2 allergenic bias is the basis of the hygiene hypothesis.

Journal Article↗

PubMed2005

Neuroimmunological findings in allergic skin diseases.

PURPOSE OF REVIEW: Recent studies have gained widespread information about the complex regulation of genetic, environmental, immunologic, and pharmacologic factors that contribute to the development of allergic inflammatory skin diseases such as atopic dermatitis. Neuroimmune mechanisms, however, still remain to be elucidated. This review will focus on the interaction between the cutaneous immune and peripheral nervous system in allergic inflammatory skin such as atopic dermatitis. RECENT FINDINGS: Neuropeptides and neuropeptide-positive nerve fibres are prominently increased in lesions of atopic dermatitis. The density of nerve fibres is increased while peripheral nerve endings are in an active state of excitation. In this regard, neurotrophins particularly described for their functional role on nerve cells are also expressed in atopic dermatitis skin. In addition, neurotrophins modulate the functional role of eosinophils as main target effector cells in atopic dermatitis, as described recently. Interestingly, eosinophils are capable of neurotrophin as well as neuropeptide production itself, pointing to a bidirectional communication between neuronal cell populations and main target effector cells. SUMMARY: Neurotrophins and neuropeptides modulate both the functional activity of sensory neurons and immune cells. We have therefore developed the concept of a neuroimmune network between target effector cells and sensory nerves that links pathogenic events to dysfunctions of the cutaneous immune and peripheral nervous system in allergic inflammatory skin diseases.

Humans↗

PubMed1998

Inducible nitric oxide synthase-deficient mice develop enhanced type 1 cytokine-associated cellular and humoral immune responses after vaccination with attenuated Schistosoma mansoni cercariae but display partially reduced resistance.

High levels of nitric oxide (NO) are produced by inducible nitric oxide synthase (iNOS) in response to activating signals from Th1-associated cytokines and play an important role in cytotoxicity and cytostasis against many pathogenic microorganisms. In addition to its direct effector function, NO serves as a potent immunoregulatory factor. NO produced by gamma interferon-activated macrophages immobilizes and kills Schistosoma mansoni larvae, and several studies have indicated a role for this pathway in protective immunity against this parasite. The potential regulatory influence of NO in immunity to S. mansoni is less well understood. In this study, we have used iNOS-deficient mice to determine the role of NO in mice vaccinated with irradiated cercariae of S. mansoni. We show by enzyme-linked immunosorbent assay and reverse transcriptase PCR analysis that vaccinated iNOS-deficient mice develop exacerbated type 1 cytokine responses in the lungs, the site where resistance to infection is primarily manifested. In addition, parasite-specific immunoglobulin G2a (IgG2a) and IgG2b antibody responses were significantly increased in vaccinated iNOS-deficient animals and total IgE antibody levels in serum were decreased relative to those in wild-type controls. Surprisingly, since resistance in this vaccine model is largely Th1 dependent and since Th1-related cellular and humoral immune responses were found to be exacerbated in vaccinated iNOS-deficient mice, vaccine-elicited protective immunity against challenge infection was found to be reduced. These findings demonstrate that iNOS plays a paradoxical role in immunity to S. mansoni, both in the effector mechanism of resistance and in the down regulation of the type 1 cytokine response, which is ultimately required for NO production.

Animals↗

PubMed2004

Antifungal immune reactivity in nasal polyposis.

As a fungal etiology has been proposed to underlie severe nasal polyposis, the present study was undertaken to assess local antifungal immune reactivity in nasal polyposis. For this purpose, microbial colonization, along with the pattern of T helper 1 (Th1)/Th2 cytokine production and Toll-like receptor (TLR) expression, was evaluated in patients with nasal symptoms and with and without polyposis and in healthy subjects. The results show that Th2 reactivity was a common finding for patients with nasal polyposis regardless of the presence of microbes. The production of interleukin-10 was elevated in patients with bacterial and, particularly, fungal colonization, while both TLR2 expression and TLR4 expression were locally impaired in microbe-colonized patients. Eosinophils and neutrophils, highly recruited in nasal polyposis, were found to exert potent antifungal effector activities toward conidia and hyphae of the fungus and to be positively regulated by TLR2 or TLR4 stimulation. Therefore, a local imbalance between activating and deactivating signals to effector cells may likely contribute to fungal pathogenicity and the expression of local immune reactivity in nasal polyposis.

Adult↗

PubMed2004

Lon protease activity causes down-regulation of Salmonella pathogenicity island 1 invasion gene expression after infection of epithelial cells.

Salmonella enterica serovar Typhimurium causes self-limiting gastroenteritis in humans and a typhoid-like disease in mice that serves as a model for typhoid infections in humans. A critical step in Salmonella pathogenesis is the invasion of enterocytes and M cells of the small intestine via expression of a type III secretion system, encoded on Salmonella pathogenicity island 1 (SPI-1), that secretes effector proteins into host cells, leading to engulfment of the bacteria within large membrane ruffles. The in vitro regulation of invasion genes has been the subject of much scientific investigation. Transcription of the hilA gene, which encodes an OmpR/ToxR-type transcriptional activator of downstream invasion genes, is increased during growth under high-osmolarity and low-oxygen conditions, which presumably mimic the environment found within the small intestine. Several negative regulators of invasion gene expression have been identified, including HilE, Hha, and Lon protease. Mutations within the respective genes increase the expression of hilA when the bacteria are grown under environmental conditions that are not favorable for hilA expression and invasion. In this study, the intracellular expression of invasion genes was examined, after bacterial invasion of HEp-2 epithelial cells, using Salmonella strains containing plasmid-encoded short-half-life green fluorescent protein reporters of hilA, hilD, hilC, or sicA expression. Interestingly, the expression of SPI-1 genes was down-regulated after invasion, and this was important for the intracellular survival of the bacteria. In addition, the effects of mutations in genes encoding negative regulators of invasion on intracellular hilA expression were examined. Our results indicate that Lon protease is important for down-regulation of hilA expression and intracellular survival after the invasion of epithelial cells.

ATP-Dependent Proteases↗

PubMed1996

Delineation and mutational analysis of the Yersinia pseudotuberculosis YopE domains which mediate translocation across bacterial and eukaryotic cellular membranes.

Pathogenic yersiniae deliver a number of different effector molecules, which are referred to as Yops, into the cytosol of eukaryotic cells via a type III secretion system. To identify the regions of YopE from Yersinia pseudotuberculosis that are necessary for its translocation across the bacterial and eukaryotic cellular membranes, we constructed a series of hybrid genes which consisted of various amounts of yopE fused to the adenylate cyclase-encoding domain of the cyclolysin gene (cyaA) of Bordetella pertussis. By assaying intact cells for adenylate cyclase activity, we show that a YopE-Cya protein containing just the 11 amino-terminal residues of YopE is efficiently exported to the exterior surface of the bacterial cell. Single amino acid replacements of the first seven YopE residues significantly decreased the amount of reporter protein detected on the cell surface, suggesting that the extreme amino-terminal region of YopE is recognized by the secretion machinery. As has recently been shown for the Y. enterocolitica YopE protein (M.-P. Sory, A. Boland, I. Lambermont, and G. R. Cornelis, Proc. Natl. Acad. Sci. USA 92:11998-12002, 1995), we found that export to the cell surface was not sufficient for YopE-Cya proteins to be delivered into the eukaryotic cytoplasm. For traversing the HeLa cell membrane, at least 49 yopE-encoded residues were required. Replacement of leucine 43 of YopE with glycine severely affected the delivery of the reporter protein into HeLa cells. Surprisingly, export from the bacterial cell was also not sufficient for YopE-Cya proteins to be released from the bacterial cell surface into the culture supernatant. At least 75 residues of YopE were required to detect activity of the corresponding reporter protein in the culture supernatant, suggesting that a release domain exists in this region of YopE. We also show that the chaperone-like protein YerA required at least 75 YopE residues to form a stable complex in vitro with YopE-Cya proteins and, furthermore, that YerA is not required to target YopE-Cya proteins to the secretion complex. Taken together, our results suggest that traversing the bacterial and eukaryotic membranes occurs by separate processes that recognize distinct domains of YopE and that these processes are not dependent on YerA activity.

Adenylyl Cyclases↗

PubMed2003

Translocated intimin receptor and its chaperone interact with ATPase of the type III secretion apparatus of enteropathogenic Escherichia coli.

Few interactions have been reported between effectors and components of the type III secretion apparatus, although many interactions have been demonstrated between type III effectors and their cognate chaperones. It is thought that chaperones may play a role in directing effectors to the type III secretion apparatus. The ATPase FliI in the flagellar assembly apparatus plays a pivotal role in interacting with other components of the apparatus and with substrates of the flagellar system. We performed experiments to determine if there were any interactions between the effector Tir and its chaperone CesT and the type III secretion apparatus of enteropathogenic Escherichia coli (EPEC). Specifically, based on analogies with the flagella system, we examined Tir-CesT interactions with the putative ATPase EscN. We showed by affinity chromatography that EscN and Tir bind CesT specifically. Tir is not necessary for CesT and EscN interactions, and EscN binds Tir specifically without its chaperone CesT. Moreover, Tir directly binds EscN, as shown via gel overlay and enzyme-linked immunosorbent assay, and coimmunoprecipitation experiments revealed that Tir interacts with EscN inside EPEC. These data provide evidence for direct interactions between a chaperone, effector, and type III component in the pathogenic type III secretion system and suggest a model for Tir translocation whereby its chaperone, CesT, brings Tir to the type III secretion apparatus by specifically interacting with the type III ATPase EscN.

Adenosine Triphosphatases↗

PubMed2004

Immunological memory to viral infections.

The purpose of immunological memory is to protect the host from reinfection, to control persistent infections, and, through maternal antibody, to protect the host's immunologically immature offspring from primary infections. Immunological memory is an exclusive property of the acquired immune system, where in the presence of CD4 T cell help, T cells and B cells clonally expand and differentiate to provide effector systems that protect the host from pathogens. Here we describe how T and B cell memory is generated in response to virus infections and how these cells respond when the host is infected again by similar or different viruses.

Animals↗