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Results for “pathogen effectors”

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PubMed2003

The role of iron in infections with intracellular bacteria.

The requirement for iron as a critical component for cellular processes has long been appreciated. During infection with intracellular bacteria, iron is required by both the host cell and the pathogen that inhabits the host cell. Macrophages require iron as a cofactor for the execution of important antimicrobial effector mechanisms, including the NADPH dependent oxidative burst and the production of nitrogen radicals catalysed by the inducible nitric oxide synthase. On the other side of the equation, intracellular bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis have an obligate requirement for iron to support their growth and survival inside cells. This brief report summarises the background to our work on iron modulation in infections with these two organisms and highlights key observations on how modulation of host iron status disturbs the equilibrium between host and pathogen and can determine the outcome of infection.

Animals↗

PubMed2004

Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination.

Preliminary observations of humoral immunity against the myelin oligodendrocyte glycoprotein (MOG) in experimental allergic encephalomyelitis (EAE) and human multiple sclerosis (MS) suggest that a subset of anti-MOG autoantibodies directed against conformational epitopes is of pathogenic predominance. Here, we provide proof that in marmoset EAE, autoantibodies reactive against conformational epitopes of MOG are not only responsible for aggravating demyelination, but also an essential factor for disease dissemination in space within the central nervous system, a hallmark for typical forms of human MS. In terms of effector mechanisms, IgG deposition and complement activation occur exclusively in association with presence of these conformational antibodies, while microglial/macrophage activation appears to be a common immunopathological finding regardless of the fine determinant specificity of anti-MOG antibodies. These findings highlight for the first time the complex heterogeneity of function and pathogenicity in the polyclonal anti-MOG antibody repertoire of outbred species. Because the linear and conformational antibody determinants of MOG are shared between marmosets and humans, these results are directly relevant to understanding effector mechanisms of organ damage in MS.

Animals↗

PubMed1992

MHC restriction of synovial fluid lymphocyte responses to the triggering organism in reactive arthritis. Absence of a class I-restricted response.

Synovial fluid mononuclear cells (SFMC) from patients with reactive arthritis (ReA) show marked proliferative responses to preparations of the organism triggering the arthritis. Initial studies with MHC-specific MoAbs have indicated that a significant element of these proliferative responses is mediated by class II MHC-restricted CD4+ T cells. It is imperative to establish the presence or absence of a class I-restricted response, for two reasons. Firstly, the association of ReA with the MHC class I molecule, HLA B27, raises the possibility of there being a B27-restricted response to the triggering organism. Secondly, a number of the organisms associated with ReA are intracellular pathogens, whose antigens might be expected to be presented by class I MHC molecules. In an effort to identify a class I MHC-restricted pathogen-specific response in the SFMC of ReA patients, we have assessed the proliferative responses of SFMC depleted of CD4+ T cells. Responses were grossly diminished by CD4+ T cell depletion. We also investigated Chlamydia-specific cytotoxicity in the SFMC of patients with sexually acquired ReA in a system using productive chlamydial infection to produce both targets and effectors. Significant antigen specific cytotoxicity was not seen. These experiments do not provide evidence to support the existence of pathogen-specific responses by CD8+, class I-restricted synovial fluid T cells in ReA.

Arthritis, Reactive↗

PubMed2005

The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention.

Salmonella is a facultative intracellular pathogen that causes diseases ranging from self-limiting enteritis to typhoid fever. This bacterium uses two type III secretion systems to deliver effector proteins directly into the host cell to promote infection and disease. Recent characterization of these virulence proteins and their host-cell targets is uncovering the molecular mechanisms of Salmonella pathogenesis and is revealing a picture of the atomic interface between this pathogen and its host. This level of analysis provides the possibility of designing novel therapeutics to disrupt infection and disease processes at the molecular level.

Actins↗

PubMed2004

Expression of human beta-defensins HBD-1, HBD-2, and HBD-3 in cultured keratinocytes and skin substitutes.

Defensins are effector molecules of the innate host defense system with antimicrobial activity against a variety of pathogens, including microorganisms commonly found in burn units. beta-Defensins are variably expressed in the epithelia of skin and other organs. Cultured skin substitutes (CSS) grafted to burn wounds lack a vascular plexus and are therefore more susceptible to microbial contamination than split thickness skin autograft. To investigate whether beta-defensins can contribute to host defense in CSS, we examined expression of human beta-defensins HBD-1, HBD-2, and HBD-3 in cultured keratinocytes and CSS from uninjured donors and burn patients. HBD-1 was expressed in all keratinocyte strains analyzed. HBD-2 expression in keratinocyte monolayers was highly variable but did not correlate with burn injury. HBD-3 was expressed at variable levels in all but one keratinocyte strain. CSS were prepared from two donors that lacked expression of HBD-2 in keratinocyte monolayers. All three genes were readily detected in CSS from both donors, suggesting up-regulation of HBD-2 and HBD-3. In sections of CSS, HBD-1, HBD-2, and HBD-3 proteins were localized to distinct epidermal regions. We conclude that beta-defensins can potentially contribute to innate immunity in CSS, but their levels may be too low to prevent contamination after grafting.

Adolescent↗

PubMed2005

Targeting of the actin cytoskeleton during infection by Salmonella strains.

Many bacterial pathogens produce virulence factors that alter the host cell cytoskeleton to promote infection. Salmonella strains target cellular actin in a carefully orchestrated series of interactions that promote bacterial uptake into host cells and the subsequent proliferation and intercellular spread of the organisms. The Salmonella Pathogenicity Island 1 (SPI1) locus encodes a type III protein secretion system (TTSS) that translocates effector proteins into epithelial cells to promote bacterial invasion through actin cytoskeletal rearrangements. SPI1 effectors interact directly with actin and also alter the cytoskeleton through activation of the regulatory proteins, Cdc42 and Rac, to produce membrane ruffles that engulf the bacteria. SPI1 also restores normal cellular actin dynamics through the action of another effector, SptP. A second TTSS, Salmonella Pathogenecity Island 2 (SPI2), translocates effectors that promote intracellular survival and growth, accompanied by focal actin polymerization around the Salmonella-containing vacuole (SCV). A number of Salmonella strains also carry the spv virulence locus, encoding an ADP-ribosyl transferase, the SpvB protein, which acts later during intracellular infection to depolymerize the actin cytoskeleton. SpvB produces a cytotoxic effect on infected host cells leading to apoptosis. The SpvB effect appears to promote intracellular infection and may facilitate cell-to-cell spread of the organism, thereby enhancing virulence.

Actins↗

PubMed2006

Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS)-like reactions.

In association with the systemic inflammatory response syndrome (SIRS), anti-inflammatory response syndrome is commonly manifested in patients with trauma, burn injury, and after major surgery. These patients are increasingly susceptible to infection with various pathogens due to the excessive release of anti-inflammatory cytokines from anti-inflammatory effector cells. Recently, CC-chemokine ligand 2 (CCL2) found in the sera of mice with pancreatitis was identified as an active molecule for SIRS-associated anti-inflammatory response manifestation. Also, the inhibitory activity of glycyrrhizin (GL) on CCL2 production was reported. Therefore, the effect of GL on SIRS-associated anti-inflammatory response manifestation was investigated in a murine SIRS model. Without any stimulation, splenic T cells from mice 5 days after SIRS induction produced cytokines associated with anti-inflammatory response manifestation. However, these cytokines were not produced by splenic T cells from SIRS mice previously treated with GL. In dual-chamber transwells, IL-4-producing cells were generated from normal T cells cultured with peripheral blood polymorphonuclear neutrophils (PMN) from SIRS mice. However, IL-4-producing cells were not generated from normal T cells in transwell cultures performed with PMN from GL-treated SIRS mice. CCL2 was produced by PMN from SIRS mice, while this chemokine was not demonstrated in cultures of PMN from SIRS mice treated with GL. These results indicate that GL has the capacity to suppress SIRS-associated anti-inflammatory response manifestation through the inhibition of CCL2 production by PMN.

Animals↗

PubMed2005

NLRs join TLRs as innate sensors of pathogens.

Pathogen-recognition receptors (PRRs) are key components of immune systems and are involved in innate effector mechanisms and activation of adaptive immunity. Since their discovery in vertebrates, Toll-like receptors (TLRs) have become the focus of extensive research that has revealed their significance in the regulation of many facets of our immune system. What makes TLRs so central and fascinating is their ability to recognize microbes and directly initiate specific signal transduction cascades that alert the host defences. In this review, we discuss the function and biology of a new family of PRRs, the NACHT-LRRs (NLRs), which include both nucleotide-binding oligomerization domains (NODs) and NALPs [NACHT-, LRR- and pyrin domain (PYD)-containing proteins], and underline some intriguing similarities between NLRs and TLRs that emphasize the role of NLRs as a complementary system for host-microbe interactions.

Adaptor Proteins, Signal Transducing↗

PubMed2006

HIV infection: first battle decides the war.

The traditional view of HIV-1 infection characterized by the slow decline of CD4+ T cells has radically changed in light of recent observations in rhesus macaques and humans of rapid and extensive infection and removal of memory CD4+ T cells in mucosal tissues within the first three weeks of infection. This initial strike to the immune system seems to be the distinguishing feature of HIV-1 pathogenesis and its extent sets the overall course of the ensuing infection. Qualitatively different mechanisms of CD4+ T-cell depletion prevail during the acute, chronic and advanced phases of infection depending on the availability of the target-cell population and competence of the immune system. The elimination of CD4+ T cells in mucosal lymphoid tissues results in the absence of important regulatory and effector functions that these cells normally perform in controlling immune responses to environmental antigens and pathogens. Ablation of acute HIV-1 viremia limits the initial damage to the CD4+ T-cell compartment and helps to establish a state of equilibrium between the replicating virus, the availability of the target-cell population and the immune control characteristic of long-term non-progression.

Animals↗

PubMed2003

Human CD8 T cells of the peripheral blood contain a low CD8 expressing cytotoxic/effector subpopulation.

Heterogeneity of lymphocyte populations demonstrates the diversity of cellular immune responses and provide a better understanding of the immune system. CD3+ CD8+ T cells exhibit a low CD8 expressing (CD8low) population in flow cytometric analysis of peripheral blood T cells. In healthy donors, this population consists of 0.2-7.0% of all CD8 T cells. The majority of the CD8low T cell population showed an elevated expression of CD25, CD45RA, and CD95L, and low levels of CD28, CD62L and CD45RO. Circulating CD8low T cells resemble cytotoxic effector cells because they express cytolytic mediators and are able to execute cytotoxicity. A restricted T cell receptor profile with increased Vbeta9, Vbeta14 and Vbeta23 expression was observed and the CD8low T cell population contain Epstein-Barr virus-specific T cells. Therefore, the CD8low population represent a subset of activated CD8 effector T cells, resulting most probably from a continuous and/or balanced immune response to intracellular pathogens.

CD8 Antigens↗

PubMed2000

Salmonella SsrB activates a global regulon of horizontally acquired genes.

Salmonella enterica is a bacterial pathogen of humans that can proliferate within epithelial cells as well as professional phagocytes of the immune system. This ability requires an S. enterica specific locus termed Salmonella pathogenicity island 2 (SPI-2). SPI-2 encodes a type III secretion system that injects effectors encoded within the island into host cell cytosol to promote virulence. SsrAB is a two-component regulator encoded within SPI-2 that was assumed to activate SPI-2 genes exclusively. Here, it is shown that SsrB in fact activates a global regulon. At least 10 genes outside SPI-2 are SsrB regulated within epithelial and macrophage cells. Nine of these 10 SsrB-regulated genes outside SPI-2 reside within previously undescribed regions of the Salmonella genome. Most share no sequence homology with current database entries. However, one is remarkably homologous to human glucosyl ceramidase, an enzyme involved in the ceramide signalling pathway. The SsrB regulon is modulated by the two-component regulatory systems PhoP/PhoQ and OmpR/EnvZ, and is upregulated in the intracellular microenvironment.

Amino Acid Sequence↗

PubMed2000

Aggregation of host endosomes by Salmonella requires SPI2 translocation of SseFG and involves SpvR and the fms-aroE intragenic region.

Salmonella-induced aggregation of host endosomal compartments into tubules, termed lgp-tubules, requires sifA and ompR. Lgp-tubules result from Salmonella-directed alteration of the endocytic system and typify the unique intracellular locale where Salmonella replicate. A high-throughput method devised to screen 11 520 MudJ mutants for loss of lgp-tubule formation identified one auxotrophic and nine prototrophic mutants. Molecular characterization identified four new loci required to alter epithelial endocytic structure. Salmonella pathogenicity island 2 (SPI2) is the locus central to the phenotype. A subset of SPI2 effectors is essential: SpiC and SseFG are required, but not SseE. A subset of apparatus proteins is also implicated: SsaJ, L, M, V and P are required. SPI2 was implicated further, as SifA shows similarity with known SPI2 translocation targets, and OmpR regulates SPI2. Another locus lies within the smf-aroE intragenic region. Lgp-tubule formation also involves a locus on the virulence plasmid pSLT. The pSLT-encoded SpvR negatively regulates an unknown repressor of the phenotype located on pSLT. Finally, disruption of carB leads to multiple auxotrophy that prevents lgp-tubule formation. This study demonstrates that lgp-tubule formation is a virulence mechanism that underlies the selective disruption of host endocytic trafficking and is associated with the formation of a replication-permissive locale.

Amino Acid Sequence↗

PubMed2003

Virulence systems of Pseudomonas syringae pv. tomato promote bacterial speck disease in tomato by targeting the jasmonate signaling pathway.

Pseudomonas syringae pv. tomato strain DC3000 (Pst DC3000) causes bacterial speck disease on tomato. The pathogenicity of Pst DC3000 depends on both the type III secretion system that delivers virulence effector proteins into host cells and the phytotoxin coronatine (COR), which is thought to mimic the action of the plant hormone jasmonic acid (JA). We found that a JA-insensitive mutant (jai1) of tomato was unresponsive to COR and highly resistant to Pst DC3000, whereas host genotypes that are defective in JA biosynthesis were as susceptible to Pst DC3000 as wild-type (WT) plants. Treatment of WT plants with exogenous methyl-JA (MeJA) complemented the virulence defect of a bacterial mutant deficient in COR production, but not a mutant defective in the type III secretion system. Analysis of host gene expression using cDNA microarrays revealed that COR works through Jai1 to induce the massive expression of JA and wound response genes that have been implicated in defense against herbivores. Concomitant with the induction of JA and wound response genes, the type III secretion system and COR repressed the expression of pathogenesis-related (PR) genes in Pst DC3000-infected WT plants. Resistance of jai1 plants to Pst DC3000 was correlated with a high level of PR gene expression and reduced expression of JA/wound response genes. These results indicate that COR promotes bacterial virulence by activating the host's JA signaling pathway, and further suggest that the type III secretion system might also modify host defense by targeting the JA signaling pathway in susceptible tomato plants.

Amino Acids↗

PubMed2000

Dendritic cells: immunological sentinels with a central role in health and disease.

Immunological effector cells must be sensitive to the antigens or environmental signals that indicate that a pathogen is present. To this end, a group of cells known as the professional antigen-presenting cells have the ability to educate T, B and NK cells as to the fingerprints of specific infections. The most adept of these cells are a closely related family termed dendritic cells (DC). A subset of these act as peripheral sentinels, specializing in the uptake, processing and presentation of antigenic material combined with an ability to detect a wide variety of 'danger' signals. These 'danger' or activation signals induce profound changes in dendritic cell physiology, facilitating the efficient stimulation of both adaptive and innate immunity. In the present review, a number of recent advances in the understanding of DC biology are discussed. These advances offer insights into the pathogenesis of a wide variety of diseases and point towards future strategies for immunotherapy.

Animals↗

PubMed1997

Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model.

Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I-restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized "naive" TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not alpha/beta-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.

Animals↗

PubMed2005

Bioinformatics correctly identifies many type III secretion substrates in the plant pathogen Pseudomonas syringae and the biocontrol isolate P. fluorescens SBW25.

The plant pathogen Pseudomonas syringae causes disease by secreting a potentially large set of virulence proteins called effectors directly into host cells, their environment, or both, using a type III secretion system (T3SS). Most P. syringae effectors have a common upstream element called the hrp box, and their N-terminal regions have amino acids biases, features that permit their bioinformatic prediction. One of the most prominent biases is a positive serine bias. We previously used the truncated AvrRpt2(81-255) effector containing a serine-rich stretch from amino acids 81 to 100 as a T3SS reporter. Region 81 to 100 of this reporter does not contribute to the secretion or translocation of AvrRpt2 or to putative effector protein chimeras. Rather, the serine-rich region from the N-terminus of AvrRpt2 is important for protein accumulation in bacteria. Most of the N-terminal region (amino acids 15 to 100) is not essential for secretion in culture or delivery to plants. However, portions of this sequence may increase the efficiency of AvrRpt2 secretion, delivery to plants, or both. Two effectors previously identified with the AvrRpt2(81-255) reporter were secreted in culture independently of AvrRpt2, validating the use of the C terminus of AvrRpt2 as a T3SS reporter. Finally, using the reduced AvrRpt2(101-255) reporter, we confirmed seven predicted effectors from P. syringae pv. tomato DC3000, four from P. syringae pv. syringae B728a, and two from P. fluorescens SBW25.

Amino Acid Sequence↗

PubMed2003

Tissue injury and repair in allografts: novel perspectives.

PURPOSE OF REVIEW: Recent research achievements might considerably alter scientific concepts of pathways involved in tissue injury and repair. RECENT FINDINGS: Accumulating evidence for an important role of alloantibodies in acute and chronic allograft rejection led to a renewed interest in humoral kidney transplant rejection. Studies reassessing the mechanisms of antibody- and complement-mediated injury now shed new light on the pathogenic mechanisms underlying acute or chronic graft dysfunction and injury. A closer look at humoral effector mechanisms revealed that endothelial cell activation and injury may play a key role in humoral rejection, and further uncovered an important interplay between humoral and cellular alloimmunity. Regeneration of cells after injury has been thought to rely on activation of local progenitor cells. Recent investigation indicates that regeneration of grafted solid organs is not exclusively based on self-renewal of tissues but obviously also involves repopulation of the graft by recipient cells, creating chimerism in the vasculature and other compartments. Besides reparative compensation of cell loss, chimerism of endothelial cells might also alter immunologic properties of the graft, thus favoring adaptation and graft survival. On the other hand, however, myofibroblasts mediating deleterious arterial intimal proliferation may also be of recipient origin. A possible source of graft-repopulating recipient cells are bone marrow-derived adult stem cells with the amazing capacity of differentiating into cell types of all three germ cell layers. SUMMARY: Reliable diagnosis of humoral mechanisms in allograft rejection and identification of involved effector mechanisms should provide the basis for development and targeted application of specific anti-humoral treatment. Recently emerged new concepts of mechanisms underlying tissue regeneration might pave the way for entirely new therapeutic approaches in human disease.

Adaptation, Physiological↗

PubMed2006

Inactivation of CD4+ CD25+ regulatory T cells during early mycobacterial infection increases cytokine production but does not affect pathogen load.

Mycobacterium tuberculosis uses numerous mechanisms to avoid elimination by the infected host. In this study, we investigated the possibility whether, similar to other pathogens, M. tuberculosis exploits natural CD4+ CD25+ T-regulatory cells (Treg) to suppress the effector function of responding host lymphocytes, thus enhancing its survival. During a Mycobacterium bovis bacille calmette guerin (BCG) pulmonary infection, we observed a 2.8-fold increase in forkhead box P3 (Foxp3+) CD25+ Treg in the lung. To inactivate the Treg in vivo, an mAb was given against CD25 (PC61) 3 days before a pulmonary infection with BCG or M. tuberculosis. Following PC61 treatment, we observed significantly decreased CD25 expression on CD4+ T lymphocytes for at least 23 days in the blood, spleen and lung when compared with the control mice. To determine whether Treg inactivation affected the protective antimycobacterial immune response, we measured cytokine production by flow cytometry. We observed small, but significant increases in the percentages of both IFN-gamma-producing and IL-2-producing CD4+ cells from the spleen and the IL-2-producing CD4+ cells from the lungs of PC61-treated BCG-infected mice compared with the infected control mice. Despite this, there was neither a difference between the lung bacterial burdens of PC61-treated mice and control mice, measured until day 44 postinfection, nor was there an effect on infection-induced lung pathology. Together, these data imply that the absence of natural Treg early after infection results in a small increase in cytokine production, but this does not alter the course of either M. tuberculosis or BCG infections. This contrasts with the important role that natural Treg play in the pathogenesis of many other intracellular infectious organisms.

Acute-Phase Reaction↗