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PubMed2003

The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases.

Pathogenic Yersinia contain a virulence plasmid that encodes genes for intracellular effectors, which neutralize the host immune response. One effector, YopM, is necessary for Yersinia virulence, but its function in host cells is unknown. To identify potential cellular pathways affected by YopM, proteins that co-immunoprecipitate with YopM in mammalian cells were isolated and identified by mass spectrometry. Results demonstrate that two kinases, protein kinase C-like 2 (PRK2) and ribosomal S6 protein kinase 1 (RSK1), interact directly with YopM. These two kinases associate only when YopM is present, and expression of YopM in cells stimulates the activity of both kinases. RSK1 is activated directly by interaction with YopM, and RSK1 kinase activity is required for YopM-stimulated PRK2 activity. YopM activation of RSK1 occurs independently of the actions of YopJ on the MAPK pathway. YopM is also required for Yersinia-induced changes in RSK1 mobility in infected macrophage cells. These results identify the first intracellular targets of YopM and suggest YopM acts to stimulate the activity of PRK2 and RSK1.

Bacterial Outer Membrane Proteins↗

PubMed2005

Glycosylation-related gene expression in prion diseases: PrPSc accumulation in scrapie infected GT1 cells depends on beta-1,4-linked GalNAc-4-SO4 hyposulfation.

Several lines of evidence indicate that some glycoconjugates are efficient effectors of the cellular prion protein (PrP(C)) conversion into its pathogenic (PrP(Sc)) isoform. To assess how glycoconjugate glycan moieties participate in the biogenesis of PrP(Sc), an exhaustive comparative analysis of the expression of about 200 glycosylation-related genes was performed on prion-infected or not, hypothalamus-derived GT1 cells by hybridization of DNA microarrays, semiquantitative RT-PCR, and biochemical assays. A significant up- (30-fold) and down- (17-fold) regulation of the expression of the ChGn1 and Chst8 genes, respectively, was observed in prion-infected cells. ChGn1 and Chst8 are involved in the initiation of the synthesis of chondroitin sulfate and in the 4-O-sulfation of non-reducing N-acetylgalactosamine residues, respectively. A possible role for a hyposulfated chondroitin in PrP(Sc) accumulation was evidenced at the protein level and by determination of chondroitin and heparan sulfate amounts. Treatment of Sc-GT1 cells with a heparan mimetic (HM2602) induced an important reduction of the amount of PrP(Sc), associated with a total reversion of the transcription pattern of the N-acetylgalactosamine-4-O-sulfotransferase 8. It suggests a link between the genetic control of 4-O-sulfation and PrP(Sc) accumulation.

Acetylgalactosamine↗

PubMed2006

The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains.

Nck proteins are essential Src homology (SH) 2 and SH3 domain-bearing adapters that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. Two mammalian pathogens, enteropathogenic Escherichia coli and vaccinia virus, exploit Nck as part of their infection strategy. Conflicting data indicate potential differences in the recognition specificities of the SH2 domains of the isoproteins Nck1 (Nckalpha) and Nck2 (Nckbeta and Grb4). We have characterized the binding specificities of both SH2 domains and find them to be essentially indistinguishable. Crystal structures of both domains in complex with phosphopeptides derived from the enteropathogenic E. coli protein Tir concur in identifying highly conserved, specific recognition of the phosphopeptide. Differential peptide recognition can therefore not account for the preference of either Nck in particular signaling pathways. Binding studies using sequentially mutated, high affinity phosphopeptides establish the sequence variability tolerated in peptide recognition. Based on this binding motif, we identify potential new binding partners of Nck1 and Nck2 and confirm this experimentally for the Arf-GAP GIT1.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Fc receptor-mediated antibody regulation of T cell immunity against intracellular pathogens.

Immunity to intracellular microbial pathogens, including Chlamydia species, is controlled primarily by cell-mediated effector mechanisms, yet, the absence of antibodies results in inefficient microbial clearance. We investigated the hypothesis that certain Fc receptor functions promote the rapid induction of elevated T helper type 1 (Th1) response, which effectively clears chlamydiae. FcR(-/-) mice exhibited a delayed and reduced frequency of Chlamydia-specific Th1 cells, compared to FcR(+/+) mice. In vitro, antichlamydial antibodies increased the rate of Th1 activation by FcR(+/+) but not FcR(-/-) antigen-presenting cells. FcR(-/-) dendritic cells and the T cell-associated IgG2A and IgA mediate enhanced Th1 activation by antibodies. Immunization with chlamydia-antibody complexes induced elevated and protective Th1 response. These results provide a mechanistic basis for requiring both T cell and humoral immune responses in protective immunity and vaccine evaluation. Findings offer a paradigm in host defense wherein different effector components function indirectly to maximize the principal effector mechanism.

Animals↗

PubMed1998

Genetically engineered antibodies in gene transfer and gene therapy.

Our ability to produce and engineer human monoclonal antibodies provides a basis for the development of novel therapeutical strategies against a variety of diseases. These strategies not only include improved passive immunotherapy but also more sophisticated antibody-based gene therapies involving gene transfer approaches. Four of the major applications of antibody gene engineering in the field of gene therapy are reviewed here. These are (1) the redefinition of viral vector tropism of infection for better transduction of cells of therapeutical interest, (2) the grafting of new cell recognition activities to effector cells of the immune system to kill cancer and pathogen-infected cells, (3) the inhibition of cellular and viral functions through intracellular expression of antibody-derived molecules, and (4) the systemic delivery of therapeutic monoclonal antibodies by non-B cells in living organisms.

Antibodies, Monoclonal↗

PubMed2025

Effectidor II: a pan-genomic AI-based algorithm for the prediction of type III secretion system effectors.

MOTIVATION: Type III secretion systems are used by many Gram-negative bacteria to inject type 3 effectors (T3Es) directly into eukaryotic cells, promoting disease or provoking immune response. Because of these opposing evolutionary forces, T3E repertoires often vary within taxonomic groups. Identifying the full effector gene repertoire in genomes of related individuals is crucial for determining core and specialized effectors, understanding the disease dynamics, and developing appropriate management strategies against pathogens. It can also help uncover novel T3Es that have recently emerged in a population. Our previously published Effectidor web server successfully addressed the challenge of identifying T3Es in a single bacterial genome. Here, we enriched the web server with various novel capabilities, including the identification of T3Es from multiple genome sequences simultaneously. RESULTS: We present Effectidor II, a web server that relies on machine learning to predict T3E-encoding genes within bacterial pan-genomes. We demonstrate the benefit of learning based on features extracted from the entire sequences comprising the pan-genome and report a novel T3E discovered by it in Xanthomonas euroxanthea. AVAILABILITY AND IMPLEMENTATION: Effectidor II is available at: https://effectidor.tau.ac.il and the source code is available at: https://github.com/naamawagner/Effectidor. A stand-alone version of Effectidor II is available at: https://github.com/naamawagner/Effectidor/tree/StandAlone. The source code for the standalone version and the data used in this work are also provided in https://doi.org/10.5281/zenodo.15081636.

Type III Secretion Systems↗

PubMed2001

A bacterial type III secretion system inhibits actin polymerization to prevent pore formation in host cell membranes.

The bacterial pathogen Yersinia pseudotuberculosis uses type III secretion machinery to translocate Yop effector proteins through host cell plasma membranes. A current model suggests that a type III translocation channel is inserted into the plasma membrane, and if Yops are not present to fill the channel, the channel will form a pore. We examined the possibility that Yops act within the host cell to prevent pore formation. Yop- mutants of Y.pseudotuberculosis were assayed for pore-forming activity in HeLa cells. A YopE- mutant exhibited high levels of pore-forming activity. The GTPase-downregulating function of YopE was required to prevent pore formation. YopE+ bacteria had increased pore-forming activity when HeLa cells expressed activated Rho GTPases. Pore formation by YopE- bacteria required actin polymerization. F-actin was concentrated at sites of contact between HeLa cells and YopE- bacteria. The data suggest that localized actin polymerization, triggered by the type III machinery, results in pore formation in cells infected with YopE- bacteria. Thus, translocated YopE inhibits actin polymerization to prevent membane damage to cells infected with wild-type bacteria.

Actins↗

PubMed2003

The HrpX/HrpY two-component system activates hrpS expression, the first step in the regulatory cascade controlling the Hrp regulon in Pantoea stewartii subsp. stewartii.

A regulatory cascade activating hrp/hrc type III secretion and effector genes was delineated in Pantoea stewartii subsp. stewartii, a bacterial pathogen of corn. Four hrp regulatory genes were characterized: hrpX and hrpY encode the sensor kinase and response regulator, respectively, of a two-component signal transduction system; hrpS encodes an NtrC-like transcriptional enhancer; and hrpL encodes an alternative sigma factor. Epistasis analysis, expression studies using gene fusions, and genetic reconstruction of each step in Escherichia coli were used to delineate the following pathway: HrpY activates hrpS and also positively autoregulates the hrpXY operon. In turn, HrpS is required for full activation of the sigma54-dependent hrpL promoter. Finally, HrpL controls expression of all known hrp and wts genes. In vitro, hrpS and all downstream hrp genes were regulated by pH and salt concentration. Mutants with in-frame deletions in hrpX were still partially virulent on corn but were unable to sense the chemical or metabolic signals that induce hrp genes in vitro. Site-directed mutagenesis of HrpY indicated that aspartate 57 is the probable phosphorylation site and that it is needed for activity. These findings suggest that both HrpX and an alternate mechanism are involved in the activation of HrpY in planta.

Amino Acid Sequence↗

PubMed2006

Bovine splenic NK cells synthesize IFN-gamma in response to IL-12-containing supernatants from Babesia bovis-exposed monocyte cultures.

The spleen is a critical effector organ functioning, in haemoparasitic diseases like babesiosis, to destroy the pathogen and clear the host of infected erythrocytes. It has an important role in both innate responses and adaptive immune responses. Young calves demonstrate a strong spleen-dependent innate response to an initial infection with Babesia bovis involving the type-1 regulating cytokines IL-12 and IFN-gamma. However, the specific splenic cell types that produce IFN-gamma in response to infection and the cellular factors that regulate the induction have not been fully determined. Splenic NKp46(+) NK cells were identified and purified. They consisted of CD3(-), CD2(+/-), and CD8(+/-) populations. NK cells responded to exogenous IL-12 and IL-18 with the production of IFN-gamma. Functionally, IL-18 served as a potent co-stimulant with IL-12 for IFN-gamma production. Finally, innate IFN-gamma production was induced in splenic NK cells in the presence of supernatants from B. bovis merozoite-exposed monocytes in an IL-12 pathway-dependent manner.

Animals↗

PubMed2005

Salmonella pathogenicity island 2-mediated overexpression of chimeric SspH2 proteins for simultaneous induction of antigen-specific CD4 and CD8 T cells.

Salmonella enterica serovar Typhimurium employs two different type III secretion systems (TTSS) encoded within Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2) for targeting of effector proteins into the cytosol of eukaryotic cells during different stages of the infection cycle. The SPI1 TTSS translocates virulence factors across the plasma membrane when the bacterium initially contacts the host cell. In contrast, the SPI2 TTSS functions to translocate proteins across the membrane of the Salmonella-containing vacuole and promotes intracellular survival and replication. The aim of the present study was to directly compare the potentials of SPI1 and SPI2 type III effector proteins to act as carrier molecules for a heterologous antigen. The p60 protein of Listeria monocytogenes was used as a model antigen to construct chimeric SopE2 (SPI1), SifA (SPI2), and SspH2 (SPI2) proteins. SPI1- and SPI2-dependent up- and down-regulation of hybrid gene expression led to sequential translocation of p60 fusion proteins into the cytosol of Salmonella-infected macrophages. Mice orally immunized with recombinant Salmonella strains expressing these hybrid proteins revealed comparable numbers of p60-specific CD8 T cells. However, only overexpression of translocated SspH2/p60 from a medium-copy-number vector induced simultaneous antigen-specific CD4 and CD8 T-cell responses, suggesting that SspH2 is an attractive carrier molecule for foreign-protein delivery.

Amino Acid Sequence↗

PubMed2001

[Structural basis of the interaction between immunoglobulins and Fc receptors provided by NMR spectroscopy].

Fc gamma Receptors (Fc gamma R) are membrane glycoproteins that bind the Fc portion of immunoglobulin G (IgG). The cross linking of Fc gamma R-bound IgG by multivalent antigens allows clustering of the Fc gamma R and initiates a variety of effector mechanisms which play a key role in immune defenses against pathogens. The Fc region is composed of two identical polypeptide chains, which are related to each other by a two-fold axis. Recent elucidation of the crystal structure of human Fc gamma RII provided two distinct views of modes of IgG-Fc gamma R interactions, which is controversial against each other. Nuclear magnetic resonance (NMR) spectroscopy provides a unique and irreplaceable tool to solve these issues. We recently studied the interaction between the Fc fragment of mouse IgG2b and the extracellular domain of mouse Fc gamma RII by this method. We showed that Fc gamma RII binds to a negatively charged area of the CH2 domain, corresponding to the lower hinge region, and that the binding of Fc gamma RII onto one of the two symmetrically related sites on the Fc induces a conformational change in the other site. This conformational change may account for the 1:1 stoichiometry that we and others observed between Fc gamma R and Fc. We therefore propose a model that explains why the interaction between IgG molecules and Fc gamma R does not trigger cellular responses in the absence of cross linking by multivalent antigens and does not lead to spontaneous inflammatory responses that would be deleterious for the organism.

Animals↗

PubMed1989

Association of activated cytolytic lung lymphocytes with response to prednisone therapy in patients with idiopathic pulmonary fibrosis.

Previous studies have suggested that immunologic mechanisms may contribute to pathogeneic reactions in certain interstitial lung diseases. Cytolytic lymphocytes are major effector cells of the immune response that have not been extensively studied in these disorders. To investigate the role of activated cytolytic lymphocytes in IPF, we studied B-cell and monocyte/macrophage-depleted lymphocyte preparations isolated from BAL fluid and peripheral blood of patients with this disease (n = 10) and used a lectin-dependent cytotoxicity assay to detect activated cytolytic lymphocytes. In longitudinal studies, those patients who had cytolytic activity of BAL fluid lymphocytes (range, 8 to 35 percent, n = 4) showed significant improvement in pulmonary function (mean increase in diffusing capacity, 30 +/- 2 percent) in association with decreased BAL fluid cytolytic lymphocyte activity after prednisone treatment. In contrast, patients who initially lacked cytolytic activity in BAL fluid (n = 6) did not improve with prednisone. Activated cytolytic lymphocytes were not observed in the BAL fluid of healthy subjects. These investigations suggest a causal relationship between activated cytolytic lymphocytes in the lung and disease activity in IPF and that assays of activated cytolytic lymphocytes are helpful in identifying patients who will improve with immunosuppressive therapy.

Antibody-Dependent Cell Cytotoxicity↗

PubMed2026

Epigenetic alterations in rheumatoid arthritis: multilayer mechanisms and translational opportunities.

Rheumatoid arthritis (RA) is a chronic inflammatory disease driven by immune dysregulation, in which genetic susceptibility and environmental exposures promote persistent synovitis, progressive joint damage, and systemic comorbidities. Recent epigenomic studies show several recurring abnormalities. Many RA susceptibility variants lie outside protein-coding sequence and map to immune-cell and synovial fibroblast regulatory elements, linking inherited risk to enhancer activity, methylation quantitative trait effects, and distal gene control. Blood-based epigenome-wide association studies identify disease-associated DNA methylation signatures, but these signals require careful control for leukocyte composition, smoking, treatment exposure, and disease stage. RA fibroblast-like synoviocytes also display stable methylome remodeling, including relative hypomethylation at loci involved in inflammation, migration, matrix degradation, and apoptosis resistance, while TET3-associated 5-hydroxymethylcytosine has emerged as a functional contributor to chemokine production and invasive stromal behavior. Histone modifications, chromatin accessibility, and 3D genome organization define pathogenic regulatory states and connect non-coding risk loci to effector genes in immune and stromal compartments. Finally, miRNAs, lncRNAs, circRNAs, snoRNAs, extracellular RNAs, and m6A-related pathways add post-transcriptional and chromatin-linked layers with potential biomarker value. We synthesize these findings and discuss translational opportunities for diagnosis, stratification, flare monitoring, and therapeutic targeting, while emphasizing incomplete replication, uneven evidence across epigenetic layers, biospecimen variability, and the need for causal, longitudinal, cell-type-resolved validation.

Humans↗

PubMed2001

Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells.

Th cell subsets, namely Th1 and Th2 cells, play an important role in mounting an immune response against invading pathogens. Several genes are selectively up-regulated during differentiation and effector phases of Th subsets. In this study, we report the identification of a novel cytokine-like molecule designated FISP (IL-4-induced secreted protein), which is selectively expressed and secreted by Th2 cells. Detectable levels of FISP are observed only 3 days after initiation of Th2 differentiation. Expression of FISP in developing Th cells requires at least two signals: TCR signaling involving protein kinase C activation and STAT6-dependent IL-4R signaling.

Amino Acid Sequence↗

PubMed2003

CpG oligodeoxynucleotides protect normal and SIV-infected macaques from Leishmania infection.

Oligodeoxynucleotides containing CpG motifs (CpG ODNs) mimic microbial DNA and activate effectors of the innate immune response, which limits the spread of pathogens and promotes an adaptive immune response. CpG ODNs have been shown to protect mice from infection with intracellular pathogens. Unfortunately, CpG motifs that optimally stimulate humans are only weakly active in mice, mandating the use of nonhuman primates to monitor the activity and safety of "human" CpG ODNs in vivo. This study demonstrates that CpG ODN treatment of rhesus macaques significantly reduces the severity of the lesions caused by a challenge with Leishmania: Leishmania superinfection is common in immunocompromised hosts, particularly those infected with HIV. This study shows that PBMCs from HIV-infected subjects respond to stimulation with CpG ODNs. To determine whether CpG ODNs can protect retrovirus-infected primates, SIV-infected macaques were treated with CpG ODNs and then challenged with Leishmania: Both lesion size and parasite load were significantly reduced in the CpG-treated animals. These findings support the clinical development of CpG ODNs as immunoprotective agents in normal and HIV-infected patients.

Adjuvants, Immunologic↗

PubMed2004

Parasite-induced Th2 polarization is associated with down-regulated dendritic cell responsiveness to Th1 stimuli and a transient delay in T lymphocyte cycling.

The nature of the signals that bias Th effector choice is still not completely understood. Using parasite extracts from pathogens known to induce polarized Th1 or Th2 responses and an in vitro experimental model for priming murine CD4(+) cells, we demonstrated that splenic dendritic cells (DC), but not B cells, promote Th1/Th2 differentiation of naive CD4(+) lymphocytes. Th polarization in this system was found not to depend on DC secretion of the polarizing cytokines IL-12/IL-4, but instead correlated with distinct states of DC activation induced by the different parasite preparations. As expected, conditioning of DC for Th1 development was associated with up-regulation of costimulatory molecules and enhanced chemokine production and required intact MyD88 signaling. In contrast, conditioning of DC for Th2 differentiation correlated with down-regulation of many of the same functions and was MyD88 independent. This dampened DC activation was accompanied in the cocultures by a reduction in the frequency of CD4(+) lymphocytes exiting the first division of the cell cycle. When the latter was mimicked by drug-induced arrest of peptide-primed CD4(+) cells after the S phase of the first cycle, a marked Th2 polarization was also observed. Together, these findings suggest that the emergence of IL-4-producing CD4(+) lymphocytes results from a suppression in DC function leading to a temporary delay in initial T cell cycling.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Immunological characterization of pulmonary intravascular macrophages.

Pulmonary intravascular macrophages (PIMs) are lung macrophages found apposed to the endothelium of pulmonary capillaries. In many species, they are responsible for the clearance of blood-borne particulates and pathogens; however, little else is known about their roles as immunologic effector cells. We compared PIMs with pulmonary alveolar macrophages (PAMs) to determine the relative immunological activities of these two cell populations. Our results suggested that both populations possess similar phagocytic and bactericidal activities. In assays measuring cytotoxicity, PIMs were more cytotoxic than PAMs against virally infected target cells; however, differences between these macrophage populations were not as marked when noninfected targets were used. LPS-stimulated PIMs produced more T-cell proliferative cytokines than PAMs, and both populations of nonstimulated macrophages produced similar amounts of the cytokines. In contrast, PAMs produced more TNF alpha and NO2- than PIMs when both populations were stimulated with LPS; however, nonstimulated PAMs and PIMs produced similar amounts of TNF alpha and NO2. These data suggest that bovine PIMs are immunologically active. Differences between the degrees of activity of PIMs and PAMs indicate that these macrophage populations may have different roles in lung surveillance.

Animals↗

PubMed2005

Genetic and environmental control of salmonella invasion.

An early step in the pathogenesis of non-typhoidal Salmonella species is the ability to penetrate the intestinal epithelial monolayer. This process of cell invasion requires the production and transport of secreted effector proteins by a type III secretion apparatus encoded in Salmonella pathogenicity island I (SPI-1). The control of invasion involves a number of genetic regulators and environmental stimuli in complex relationships. SPI-1 itself encodes several transcriptional regulators (HilA, HilD, HilC, and InvF) with overlapping sets of target genes. These regulators are, in turn, controlled by both positive and regulators outside SPI-1, including the two-component regulators BarA/SirA and PhoP/Q, and the csr post-transcriptional control system. Additionally, several environmental conditions are known to regulate invasion, including pH, osmolarity, oxygen tension, bile, Mg2+ concentration, and short chain fatty acids. This review will discuss the current understanding of invasion control, with emphasis on the interaction of environmental factors with genetic regulators that leads to productive infection.

Animals↗