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At least 937 records · Page 52Linked to original sources

PubMed2005

Tuning of macrophage responses by Stat3-inducing cytokines: molecular mechanisms and consequences in infection.

A successful response to pathogen challenge requires that a balance is achieved between the induction of efficient anti-microbial effector mechanisms and the avoidance of detrimental tissue damage. While the Toll-like receptor (TLR) system is innate immunity's sensor of infectious danger, macrophages receive activating as well as inhibitory signals via the Jak-Stat pathway. IFNgamma is key to the control of infection particularly with intracellular pathogens and depends on functional Stat1 signal transduction. Stat3 signalling is activated by a range of cytokines, including IL-10, IL-6 and IL-27. Here, recent progress in understanding the regulation of macrophage function in inflammation and infection by Stat3-activating cytokines is reviewed. The use of targeted mouse mutants of these cytokines, their receptors or signalling components, revealed the importance of the Stat3 axis in the control of infection and immunopathology. Genome-wide transcriptome analyses of macrophages under the influence of these cytokines have contributed to advances in defining the molecular mechanisms of macrophage activation and deactivation. Functional characterization of Stat3-target genes should now identify the molecular mediators of impaired pathogen control and tissue protection.

Animals↗

PubMed2000

Myelin reactive T cells after T cell vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations.

Pathogenic autoreactive T cells can be targeted by T cell vaccination (TCV), a procedure in which patients are immunized with autologous attenuated pathogenic T cells. We reported previously that TCV with myelin basic protein (MBP) reactive T cell clones in multiple sclerosis (MS) patients induced T cell immune responses, resulting in a clonal depletion of MBP reactive T cells in all patients. Five years after TCV, MBP reactive T cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before vaccination. We have studied the cytokine profile, cytotoxicity and epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a pathogenic role in the disease. We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T cell targeted immunotherapies for MS and other autoimmune diseases.

Clone Cells↗

PubMed2005

Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG.

EspG is a conserved protein encoded by the locus of enterocyte effacement (LEE) of attaching and effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli and Citrobacter rodentium. EspG is delivered into infected host cells by a type III secretion system. The role of EspG in virulence has not yet been defined. Here we describe experiments that probe the virulence characteristics and biological activities of EspG in vitro and in vivo. A C. rodentium espG mutant displayed a significantly reduced ability to colonize C57BL/6 mice and to cause colonic hyperplasia. Epitope-tagged EspG was detected in the apical regions of infected colonic epithelial cells in infected mice, partially localizing with another LEE-encoded effector protein, Tir. EspG was found to interact with mammalian tubulin in both genetic screens and gel overlay assays. Binding to tubulin by EspG caused localized microtubule depolymerization, resulting in actin stress fiber formation through an undefined mechanism. Heterologous expression of EspG in yeast resulted in loss of cytoplasmic microtubule structure and function, preventing coordination between bud development and nuclear division. Yeast expressing EspG were also unable to control cortical actin polarity. We suggest that EspG contributes to the ability of A/E pathogens to establish infection through a modulation of the host cytoskeleton involving transient microtubule destruction and actin polymerization in a manner akin to the Shigella flexneri VirA protein.

Actins↗

PubMed2005

Enteropathogenic Escherichia coli type III effectors alter cytoskeletal function and signalling in Saccharomyces cerevisiae.

Enteropathogenic Escherichia coli (EPEC) strains cause attaching/effacing lesions in enterocytes through the development of actin-supported pedestals at the site of bacterial adhesion. Pathogenesis requires a type III secretion system (TTSS), which injects into the host cell the intimin receptor, Tir, as well as other effectors called Esps (Escherichia secreted proteins). The genes encoding TTSS structural components and Esps are found within a pathogenicity island called the locus of enterocyte effacement (LEE). This paper describes the application of Saccharomyces cerevisiae as a model to probe the functions of LEE-encoded genes. In a systematic approach, the LEE-encoded translocator and effector proteins were endogenously expressed in yeast and their effects on cell growth, cytoskeletal function and signalling pathways were studied. EspD, EspG and Map inhibited growth by depolarizing the actin cortical cytoskeleton, whereas EspF expression altered the septin cytoskeleton. Specific yeast MAP kinase pathways were activated by EspF, EspG, EspH and Map. The yeast system was used to define functional domains in Map by expressing truncated versions; it was concluded that the C-terminal region of the protein is necessary for actin disruption and toxicity, but not for mitochondrial localization. The utility of the yeast model for functional analyses of EPEC pathogenesis is discussed.

Actins↗

PubMed2003

T lymphocytes.

T cells are major players in the adaptive immune response to pathogens. They express clonally distributed, highly polymorphic antigen receptors that enable them to recognize cell-associated antigen. Upon antigen recognition, T cells undergo clonal amplification and progressively acquire effector functions, ranging from the production of paracrine soluble factors that provide "help" to other immune cells to the ability to kill pathogen-infected cells with surgical precision. A pool of antigen-reactive T cells reverts to a state of quiescence and maintains a long-lasting memory of antigen encounter. T cells develop in the thymus through a rigorous selection process that recapitulates Darwinian phylogenesis: only the "fittest" survive, i.e. those that can efficiently recognize infectious non-self-antigens but ignore, or are silenced, by non-infectious self-antigens. Due to their ability to discriminate between self and non-self, T cells are the major effectors of allograft rejection. T cells are involved in the pathogenesis of several human disorders, resulting from their defective or dysregulated function. The former leads to a severe state of immunodeficiency, the latter to organ-specific or systemic autoimmunity.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Host immunity to ticks.

The tick-host-pathogen interface is characterized by complex immunological interactions. Tick feeding induces host immune regulatory and effector pathways involving antibodies, complement, antigen-presenting cells, T lymphocytes, and other bioactive molecules. Acquired resistance impairs tick engorgement, ova production, and viability. Tick countermeasures to host defenses reduce T-lymphocyte proliferation, elaboration of the TH1 cytokines interleukin-2 and interferon-gamma, production of macrophage cytokines interleukin-1 and tumor necrosis factor, and antibody responses. The dynamic balance between acquired resistance and tick modulation of host immunity affects engorgement and pathogen transmission. A thorough understanding of acquired immunity to ticks is essential for rational development of antitick vaccines.

Animals↗

PubMed2005

Mast cells in the development of adaptive immune responses.

Mast cells are so widely recognized as critical effector cells in allergic disorders and other immunoglobulin E-associated acquired immune responses that it can be difficult to think of them in any other context. However, mast cells also can be important as initiators and effectors of innate immunity. In addition, mast cells that are activated during innate immune responses to pathogens, or in other contexts, can secrete products and have cellular functions with the potential to facilitate the development, amplify the magnitude or regulate the kinetics of adaptive immune responses. Thus, mast cells may influence the development, intensity and duration of adaptive immune responses that contribute to host defense, allergy and autoimmunity, rather than simply functioning as effector cells in these settings.

Animals↗

PubMed2002

Differential regulation of the mitogen-activated protein kinases by pathogenic and nonpathogenic mycobacteria.

Mycobacteria are the etiologic agents of numerous diseases which account for significant morbidity and mortality in humans and other animal species. Many mycobacteria are intramacrophage pathogens and therefore the macrophage response to infection, which includes synthesis of cytokines such as tumor necrosis factor alpha (TNF-alpha) and production of nitric oxide, has important consequences for host immunity. However, very little is known about the macrophage cell signaling pathways initiated upon infection or how pathogenic mycobacteria may modulate the macrophage responses. Using primary murine bone marrow macrophages, we established that p38 and extracellular signal-regulated kinases 1 and 2 of the mitogen-activated protein kinase (MAPK) pathways are activated upon infection with different species of mycobacteria. However, we observed decreased MAPK activity over time in macrophages infected with pathogenic Mycobacterium avium strains relative to infections with nonpathogenic mycobacteria. Furthermore, macrophages infected with M. avium produced lower levels of TNF-alpha, interleukin 1beta, and inducible nitric oxide synthase 2 than macrophages infected with nonpathogenic species. Inhibitor studies indicate that the MAPKs are required for the Mycobacterium-mediated induction of these effector proteins. Our data indicate that MAPKs are activated in macrophages upon invasion by mycobacteria and that this activation is diminished in macrophages infected with pathogenic strains of M. avium, resulting in decreased production of important immune effector proteins. The decreased MAPK activation associated with M. avium infections suggests a novel point of immune intervention by this mycobacterial species.

Animals↗

PubMed1994

Cell-mediated immune effector functions in chickens.

Cell-mediated immune responses form an important part of the protection against intracellular pathogens. The MHC Class I and Class II antigens are important for the proper presentation of degraded proteins to cytotoxic T lymphocytes (CTL) and helper T cells, respectively. Recent developments in the knowledge of the molecular structure of the MHC in relation to antigen presentation are discussed. Although CTL are important, there is a paucity of information concerning their relevance for the control of viral diseases in poultry. A newly developed approach of stable transfection of viral genes into cell lines transformed by reticuloendotheliosis virus has shown promise as a method to define proteins, which are important for the induction of cell-mediated immunity.

Animals↗

PubMed2000

Correlation of susceptibility of immature mice to fungal infection (blastomycosis) and effector cell function.

Immature mice are highly susceptible to blastomycosis, which is similar to other mycoses and has parallels in humans. The murine susceptibility is noteworthy in that it persists beyond the development of resistance to other, nonfungal pathogens and the maturation of most immune functions. As the susceptibility to blastomycosis appeared to be related to an early event after infection, primary effector cell function was studied. We found that peritoneal inflammatory cells, enriched for neutrophils, from immature (3-week-old) mice killed nonphagocytizable Blastomyces dermatitidis cells less (25%) than did cells from mature (8-week) mice (70%) (P<0.01), a defect intrinsic to the neutrophils. This correlated with an impaired immature cell oxidative burst. Killing of phagocytizable Candida albicans was not significantly different, 73 versus 87%. Thioglycolate-elicited cells were more impaired; killing of B. dermatitidis was insignificant, and killing of C. albicans was more impaired in immature (16% killing) than in mature (45%) cells (P<0.02). Peripheral blood neutrophils from mature animals killed B. dermatitidis (41%) more than did those from immature animals (10%) (P<0.02); C. albicans was killed efficiently by both. Resting or activated peritoneal macrophages from both types of animals showed no differences in B. dermatitidis killing. These results suggest that the susceptibility of immature mice is related at least in part to the depressed capacity of their neutrophils to kill B. dermatitidis.

Age Factors↗

PubMed2001

Common and contrasting themes of plant and animal diseases.

Recent studies in bacterial pathogenesis reveal common and contrasting mechanisms of pathogen virulence and host resistance in plant and animal diseases. This review presents recent developments in the study of plant and animal pathogenesis, with respect to bacterial colonization and the delivery of effector proteins to the host. Furthermore, host defense responses in both plants and animals are discussed in relation to mechanisms of pathogen recognition and defense signaling. Future studies will greatly add to our understanding of the molecular events defining host-pathogen interactions.

Amino Acid Sequence↗

PubMed2025

Efficient genome editing in Pseudomonas syringae pv. actinidiae using the CRISPR/FnCas12a system.

CRISPR-based gene editing has rarely been studied in plant pathogens. In this report, the CRISPR/FnCas12a system was successfully established for gene editing in Pseudomonas syringae pv. actinidiae (Psa), which causes bacterial canker (BC) of kiwifruit. The system was constructed in a Psa-suitable vector pBBR1-MCS2 to edit hopH1 or/and hopZ5, which encode effectors only present in Psa biovar 3 (Psa3) responsible for BC pandemic in kiwifruit worldwide. Two different CRISPR RNAs (crRNA) were designed to edit either hopH1 or/and hopZ5, and two different sets of PCR primers were used to screen deletions of the target genes and the presence of the vector in Psa. The deletion in Psa was impacted by the position of the DNAs targeted by the crRNAs. The vector-eliminated mutant could receive the editing system iteratively. Interestingly, the double mutant ΔhopZ5ΔhopH1 showed significantly stronger virulence than the wild-type Psa on Actinidia eriantha cv. White (resistant to BC), but weak virulence on A. chinensis cv. Hongyang (highly susceptible to BC), respectively, suggesting that hopH1 or/and hopZ5 potentially matches an unknown resistance gene in White. In summary, we have established the CRISPR/FnCas12a genome-editing system to probe gene function in the pathogen and to explore effector-target interactions in kiwifruit-Psa-pathosyetem.

Bacterial canker↗

PubMed2004

Type III protein secretion mechanism in mammalian and plant pathogens.

The type III protein secretion system (TTSS) is a complex organelle in the envelope of many Gram-negative bacteria; it delivers potentially hundreds of structurally diverse bacterial virulence proteins into plant and animal cells to modulate host cellular functions. Recent studies have revealed several basic features of this secretion system, including assembly of needle/pilus-like secretion structures, formation of putative translocation pores in the host membrane, recognition of N-terminal/5' mRNA-based secretion signals, and requirement of small chaperone proteins for optimal delivery and/or expression of effector proteins. Although most of our knowledge about the TTSS is derived from studies of mammalian pathogenic bacteria, similar and unique features are learned from studies of plant pathogenic bacteria. Here, we summarize the most salient aspects of the TTSS, with special emphasis on recent findings.

Animals↗

PubMed2004

STAT1 is essential for antimicrobial effector function but dispensable for gamma interferon production during Toxoplasma gondii infection.

The opportunistic protozoan Toxoplasma gondii is a prototypic Th1-inducing pathogen inducing strong gamma interferon (IFN-gamma) cytokine responses that are required to survive infection. Intracellular signaling intermediate STAT1 mediates many effects of IFN-gamma and is implicated in activation of T-bet, a master regulator of Th1 differentiation. Here, we show that T. gondii-infected STAT1-null mice fail to upregulate the IFN-gamma-dependent effector molecules inducible nitric oxide synthase (iNOS), IGTP, and LRG-47, which are required for mice to survive infection. Both T-bet and interleukin-12 receptor beta2 (IL-12Rbeta2) failed to undergo normal upregulation in response to T. gondii. Development of IFN-gamma-producing CD4(+) and CD8(+) T lymphocytes was severely curtailed in the absence of STAT1, but a substantial level of STAT1-independent non-T-cell-derived IFN-gamma was induced. Absence of STAT1 also resulted in increased IL-4, Arg1, Ym1, and Fizz1, markers of Th2 differentiation and alternative macrophage activation. Together, the results show that T. gondii induces STAT1-dependent T-lymphocyte and STAT1-independent non-T-cell IFN-gamma production, but that effector functions of this type 1 cytokine cannot operate in the absence of STAT1, resulting in extreme susceptibility to acute infection.

Animals↗

PubMed2001

HrpZ(Psph) from the plant pathogen Pseudomonas syringae pv. phaseolicola binds to lipid bilayers and forms an ion-conducting pore in vitro.

The hrp gene clusters of plant pathogenic bacteria control pathogenicity on their host plants and ability to elicit the hypersensitive reaction in resistant plants. Some hrp gene products constitute elements of the type III secretion system, by which effector proteins are exported and delivered into plant cells. Here, we show that the hrpZ gene product from the bean halo-blight pathogen, Pseudomonas syringae pv. phaseolicola (HrpZ(Psph)), is secreted in an hrp-dependent manner in P. syringae pv. phaseolicola and exported by the type III secretion system in the mammalian pathogen Yersinia enterocolitica. HrpZ(Psph) was found to associate stably with liposomes and synthetic bilayer membranes. Under symmetric ionic conditions, addition of 2 nM of purified recombinant HrpZ(Psph) to the cis compartment of planar lipid bilayers provoked an ion current with a large unitary conductivity of 207 pS. HrpZ(Psph)-related proteins from P. syringae pv. tomato or syringae triggered ion currents similar to those stimulated by HrpZ(Psph). The HrpZ(Psph)-mediated ion-conducting pore was permeable for cations but did not mediate fluxes of Cl-. Such pore-forming activity may allow nutrient release and/or delivery of virulence factors during bacterial colonization of host plants.

Animals↗

PubMed1998

Salmonella InvG forms a ring-like multimer that requires the InvH lipoprotein for outer membrane localization.

Salmonella species translocate virulence effector proteins from the bacterial cytoplasm into mammalian host cells by means of a type III secretion apparatus, encoded by the pathogenicity island-1 (SPI-1). Little is known about the assembly and structure of this secretion apparatus, but the InvG protein is essential and could be an outer membrane secretion channel for the effector proteins. We observed that in recombinant Escherichia coli, the yield of InvG was enhanced by co-expression of InvH, and showed that mutation of invH decreased the level of InvG in wild-type Salmonella typhimurium. In E. coli, InvG alone was able to form an SDS-resistant multimer, but InvG localization to the outer membrane was dependent upon InvH, a lipoprotein itself located in the outer membrane, and no other SPI-1 specific protein. InvG targeted to the outer membrane by InvH became accessible to extracellular protease. InvG and InvH did not, however, appear to form a stable complex. Electron microscopy of InvG membrane protein purified from E. coli revealed that it forms an oligomeric ring-like structure with inner and outer diameters, 7 nm and 15 nm respectively.

Bacterial Outer Membrane Proteins↗

PubMed2004

Crystal structures of the type III effector protein AvrPphF and its chaperone reveal residues required for plant pathogenesis.

The avrPphF locus from Pseudomonas syringae pv. phaseolicola, the causative agent of bean halo-blight disease, encodes proteins which either enhance virulence on susceptible hosts or elicit defense responses on hosts carrying the R1 resistance gene. Here we present the crystal structures of the two proteins from the avrPphF operon. The structure of AvrPphF ORF1 is strikingly reminiscent of type III chaperones from bacterial pathogens of animals, indicating structural conservation of these specialized chaperones, despite high sequence divergence. The AvrPphF ORF2 effector adopts a novel "mushroom"-like structure containing "head" and "stalk" subdomains. The head subdomain possesses limited structural homology to the catalytic domain of bacterial ADP-ribosyltransferases (ADP-RTs), though no ADP-RT activity was detected for AvrPphF ORF2 in standard assays. Nonetheless, this structural similarity identified two clusters of conserved surface-exposed residues important for both virulence mediated by AvrPphF ORF2 and recognition of this effector by bean plants expressing the R1 resistance gene.

ADP Ribose Transferases↗

PubMed1992

Synthetic peptides as vaccines.

The economics of vaccines has been a major limitation in the commercial research and development of new approaches. This coupled with the natural scientific desire to simplify and define the composition of effective vaccines argues that the future of vaccines lies in novel approaches that will discover effective and less expensive components. Peptides, whether they are chemically synthesized or produced in bacteria, are an attractive possibility. To substitute linear peptides for complex mixtures of proteins would be a major technical advance and would stimulate tremendous commercial interest. However, at the present time I view this approach still unlikely to be of major practical importance. I conclude this because of the complexity of immunological responses to microorganisms. Even though, in some instances, a cytotoxic T-cell response or even the majority of the antibody response to a pathogen can be defined by a short linear peptide, most people believe that multiple effector functions of the immune system should be stimulated in optimal vaccines. For a small cocktail of peptides to reproduce the diversity of responses elicited by a virus, parasite, or bacterium is unlikely. However, I fully realize that remarkable progress has occurred towards understanding the structural requirements necessary to stimulate cellular and humoral immune responses, and peptides have been integral in the development of this field. Also, the success of several research groups in developing effective antiviral vaccines using short linear peptides argues that I might be painting too dark of a picture. As someone who has used this strategy to explore peptide-MHC and peptide-antibody interactions, I am a strong scientific supporter of the approach. In this forum I am purposely cautious in my optimism. As the details of the complex molecular and cellular interactions that control the immune system are elucidated, both the number of strategies and the possible applications of modulating the immune response will increase as well. In addition to protective immunity to pathogens, cancer therapy could be revolutionized if tumor-specific cytotoxic T-cells could be generated routinely. Novel therapeutic approaches to allergy, autoimmunity, and transplantation can be envisioned if the T-lymphocytes responsible for these syndromes could be modulated without total immune suppression. Consequently, I am confident that the experiments described in this chapter will be central to developing exciting new therapeutic and prophylactic compounds, but I am not sure that they will resemble naturally occurring peptides. The one aspect I am confident of is that the capacity of the immune response to protect the organism will continually surprise us.

Animals↗