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PubMed2006

Transcriptional regulation of the Pseudomonas aeruginosa type III secretion system.

Type III secretion systems (T3SS) function by translocating effector proteins into eukaryotic host cells and are important for the virulence of many Gram-negative bacterial pathogens. Although the secretion and translocation machineries are highly conserved between different species, each pathogen translocates a unique set of effectors that subvert normal host cell physiology to promote pathogenesis. The uniqueness of each pathogen is further reflected in the diversity of mechanisms used to regulate T3SS gene expression. Pseudomonas aeruginosa utilizes a complex set of signalling pathways to modulate T3SS expression in response to extracellular and intracellular cues. Whereas some pathways are dedicated solely to regulating the T3SS, others co-ordinately regulate expression of the T3SS with multiple virulence functions on a global scale. Emerging regulatory themes include coupling of T3SS transcription with type III secretory activity, global regulatory control through modulation of cAMP biosynthesis, repression by a variety of stresses, involvement of multiple two component regulatory systems, and an inverse relationship between T3SS expression and multicellular behaviour. Factors controlling activation of T3SS expression likely contribute to the environmental survival of the organism and to the pathogenesis of acute P. aeruginosa infections. Conversely, active repression of the T3SS might contribute to the persistence of chronic infections.

Bacterial Proteins↗

PubMed2006

A Pseudomonas syringae pv. tomato avrE1/hopM1 mutant is severely reduced in growth and lesion formation in tomato.

The model plant pathogen Pseudomonas syringae pv. tomato DC3000 grows and produces necrotic lesions in the leaves of its host, tomato. Both abilities are dependent upon the hypersensitive response and pathogenicity (Hrp) type III secretion system (TTSS), which translocates multiple effector proteins into plant cells. A previously constructed DC3000 mutant with a 9.3-kb deletion in the Hrp pathogenicity island conserved effector locus (CEL) was strongly reduced in growth and lesion formation in tomato leaves. The ACEL mutation affects three putative or known effector genes: avrE1, hopM1, and hopAA1-1. Comparison of genomic sequences of DC3000, P. syringae pv. phaseolicola 1448A, and P. syringae pv. syringae B728a revealed that these are the only effector genes present in the CEL of all three strains. AvrEl was shown to carry functional TTSS translocation signals based on the performance of a fusion of the first 315 amino acids of AvrE1 to the Cya translocation reporter. A DC3000 delta avrE1 mutant was reduced in its ability to produce lesions but not in its ability to grow in host tomato leaves. AvrE1 expressed from the 35S promoter elicited cell death in nonhost Nicotiana tabacum leaves and host tomato leaves in Agrobacterium-mediated transient expression experiments. Mutations involving combinations of avrE1, hopM1, and hopAA1-1 revealed that deletion of both avrE1 and hopM1 reproduced the strongly reduced growth and lesion phenotype of the delta CEL mutant. Furthermore, quantitative assays involving different levels of inoculum and electrolyte leakage revealed that the avrE1/hopM1 and deltaCEL mutants both were partially impaired in their ability to elicit the hypersensitive response in nonhost N. benthamiana leaves. However, the avrE1/hopM1 mutant was not impaired in its ability to deliver AvrPto1(1-100)-Cya to nonhost N. benthamiana or host tomato leaves during the first 9 h after inoculation. These data suggest that AvrE1 acts within plant cells and promotes lesion formation and that the combined action of AvrE1 and HopM1 is particularly important in promoting bacterial growth in planta.

Cell Death↗

PubMed2003

Common infection strategies of plant and animal pathogenic bacteria.

Gram-negative bacterial pathogens use common strategies to invade and colonize plant and animal hosts. In many species, pathogenicity depends on a highly conserved type-III protein secretion system that delivers effector proteins into the eukaryotic cell. Effector proteins modulate a variety of host cellular pathways, such as rearrangements of the cytoskeleton and defense responses. The specific set of effectors varies in different bacterial species, but recent studies have revealed structural and functional parallels between some effector proteins from plant and animal pathogenic bacteria. These findings suggest that bacterial pathogens target similar pathways in plant and animal host cells.

Animals↗

PubMed1999

Isolation of a temperate bacteriophage encoding the type III effector protein SopE from an epidemic Salmonella typhimurium strain.

Salmonella typhimurium employs the specialized type III secretion system encoded in pathogenicity island 1 (SPI1) to translocate effector proteins into host cells and to modulate host cell signal transduction. The SPI1 type III system and the effector proteins are conserved among all salmonellae and are thought to be acquired by horizontal gene transfer. The genetic mechanisms mediating this horizontal transfer are unknown. Here, we describe that SopE, a SPI1-dependent translocated effector protein, is present in relatively few S. typhimurium isolates. We have isolated a temperate phage that encodes SopE. Phage morphology and DNA hybridization, as well as partial sequence information, suggest that this phage (SopEPhi) is a new member of the P2 family of bacteriophages. By lysogenic conversion this phage can horizontally transfer genes between different S. typhimurium strains. Strikingly, most of the isolates harboring SopEPhi belong to the small group of epidemic strains of S. typhimurium that have been responsible for a large percentage of human and animal salmonellosis and have persisted for a long period of time. Our data suggest that horizontal transfer of type III dependent effector proteins by lysogenic infection with bacteriophages (lysogenic conversion) may provide an efficient mechanism for fine-tuning the interaction of Salmonella spp. with their hosts.

Bacterial Proteins↗

PubMed2006

Making sense of inflammation, epigenetics, and memory CD8+ T-cell differentiation in the context of infection.

Recent findings suggest a new paradigm that early inflammatory cytokines promote the effector T-cell response while inhibiting the development of CD8+ T-cell memory. Although this opposing effect may appear paradoxical at first, it makes biological sense in the context of an infection, by ensuring a maximal effector response that will clear the pathogen. Once infection is controlled, the withdrawal of inflammatory cytokines allows the differentiation of effectors into long-lived memory cells that provide protective immunity against re-infection. Memory T cells differ from naïve T cells in their responsiveness to stimulation, which leads to the rapid expression of effector functions. The molecular basis for enhanced functionality of memory T cells remains largely unknown. Recent results indicate that certain epigenetic changes are imprinted in memory T cells that play an important role in keeping them poised to respond immediately upon antigen re-encounter. These epigenetic modifications occur as naïve T cells become activated and are influenced by factors that regulate memory formation. Thus, epigenetic changes are an integral component of memory T-cell differentiation, while inflammation plays an unexpected regulatory role in the process. These advances in our understanding of T-cell memory will undoubtedly help design unconventional vaccine strategies for inducing large populations of long-lived and functional memory CD8+ T cells.

CD8-Positive T-Lymphocytes↗

PubMed2004

Dissecting virulence: systematic and functional analyses of a pathogenicity island.

Bacterial pathogenicity islands (PAI) often encode both effector molecules responsible for disease and secretion systems that deliver these effectors to host cells. Human enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli, and the mouse pathogen Citrobacter rodentium (CR) possess the locus of enterocyte effacement (LEE) PAI. We systematically mutagenized all 41 CR LEE genes and functionally characterized these mutants in vitro and in a murine infection model. We identified 33 virulence factors, including two virulence regulators and a hierarchical switch for type III secretion. In addition, 7 potential type III effectors encoded outside the LEE were identified by using a proteomics approach. These non-LEE effectors are encoded by three uncharacterized PAIs in EHEC O157, suggesting that these PAIs act cooperatively with the LEE in pathogenesis. Our findings provide significant insights into bacterial virulence mechanisms and disease.

Animals↗

PubMed2002

Salmonella selectively stops traffic.

The intracellular pathogen Salmonella replicates in infected host cells within a specialized vacuole referred to as the Salmonella-containing vacuole (SCV). Effector molecules encoded by the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS) are essential for Salmonella to survive in the intracellular environment. It was previously shown that SPI-2 allows Salmonella to inhibit the recruitment of NADPH phagocyte oxidase-containing vesicles to SCVs. New research has now revealed that SPI-2 effectors also interfere with the colocalization of inducible nitric oxide synthase (iNOS) to SCVs, thus protecting the pathogen from the antimicrobial actions of reactive nitrogen species.

Bacterial Proteins↗

PubMed1998

Skin delivery of a hybrid liposome/ISCOM vaccine implicates a role for adjuvants in rapid modulation of inflammatory cells involved in innate immunity before the enhancement of adaptive immune responses.

There is now compelling evidence that intradermal vaccination with an efficacious adjuvanted antigen triggers a series of coordinated responses characterized initially by the rapid mobilization and recruitment of granulocytes to the lung. Activation of effector cells of the innate immune system is intended to provide surveillance and temporary protective cover at vulnerable mucosal sites while both T and B cell precursors, as well as haematopoietic progenitor cells, are undergoing dramatic reductions in numbers during the first 2-4 days post-vaccination. Some of these events recapitulate those seen after infection with a pathogen. Initial decreases in cell numbers in the thymus and bone marrow (BM) are followed by rapid increases in cellular proliferation in these organs, probably in response to peripheral signals. Vaccine-induced cell death (by apoptosis) in the thymus may provide one of many stimuli needed to up-regulate BM production of progenitor cells, and cells of the B, myeloid and monocytic lineages so that depleted peripheral compartments are replenished. Reconstitution of the latter cell population is critical in ensuring sufficient numbers of APC are generated to deal with extraneous antigen resulting from either vaccination or proliferation of a pathogen. Ultimately, these APC, as effector cells of the innate immune system, must provide pattern recognition of dangerous pathogens and serve to activate appropriate T cell responses. Vaccination not only educates both the innate and adaptive arms of the immune response but also more interestingly, appears to regulate subsequent innate immune responses following exposure to a lethal challenge dose of bacteria. Under these conditions, the rate of loss of BM precursors is greatly attenuated in mice previously vaccinated with adjuvanted antigen compared to unvaccinated controls or mice that had received only antigen. Mice intradermally vaccinated with adjuvanted antigen also displayed increased rates of granulocyte and monocyte recruitment in the lung and spleen. These events occurred very rapidly within 12-36 h of challenge and may be crucial in providing complete protection in vaccinated mice against a challenge dose that was otherwise lethal for unvaccinated controls. Therefore, an important characteristic of an efficacious intradermal vaccine may be the ability to deplete T and B precursors in the thymus and BM lymphoid compartments followed by increased rates of haematopoiesis to re-supply peripheral requirements for granulocytes/monocytes, and T and B cells. Adaptive immunity elicited by intradermal vaccination is, therefore, dependent upon prior activation of the innate immune system.

Adjuvants, Immunologic↗

PubMed2002

Identification of novel hrp-regulated genes through functional genomic analysis of the Pseudomonas syringae pv. tomato DC3000 genome.

Pseudomonas syringae pv. tomato (Pst) strain DC3000 infects the model plants Arabidopsis thaliana and tomato, causing disease symptoms characterized by necrotic lesions surrounded by chlorosis. One mechanism used by Pst DC3000 to infect host plants is the type III protein secretion system, which is thought to deliver multiple effector proteins to the plant cell. The exact number of type III effectors in Pst DC3000 or any other plant pathogenic bacterium is not known. All known type III effector genes of P. syringae are regulated by HrpS, an NtrC family protein, and the HrpL alternative sigma factor, which presumably binds to a conserved cis element (called the "hrp box") in the promoters of type III secretion-associated genes. In this study, we designed a search motif based on the promoter sequences conserved in 12 published hrp operons and putative effector genes in Pst DC3000. Seventy-three predicted genes were retrieved from the January 2001 release of the Pst DC3000 genome sequence, which had 95% genome coverage. The expression of the 73 genes was analysed by microarray and Northern blotting, revealing 24 genes/operons (including eight novel genes), the expression of which was consistently higher in hrp-inducing minimal medium than in nutrient-rich Luria-Bertani broth. Expression of all eight genes was dependent on the hrpS gene. Most were also dependent on the hrpL gene, but at least one was dependent on the hrpS gene, but not on the hrpL gene. An AvrRpt2-based type III translocation assay provides evidence that some of the hrpS-regulated novel genes encode putative effector proteins.

Arabidopsis↗

PubMed2006

Stat1 deficiency exacerbates carditis but not arthritis during experimental lyme borreliosis.

Activation of the transcription factor Stat1 by interferon-gamma (IFN-gamma) is an important step in the development of antimicrobial effector mechanisms against many bacterial pathogens. Susceptibility to murine Lyme arthritis has been correlated with the production of several proinflammatory cytokines, especially IFN-gamma. To determine the role of IFN-mediated effector mechanisms in the development of Lyme borreliosis, we infected Stat1-deficient mice on both resistant (DBA), and susceptible (C3H) genetic backgrounds. Arthritis in Stat1(/) mice was similar to that of wild-type controls in both mouse strains. Spirochete loads in tissues were also unchanged in Stat1(/) mice. C3H Stat1(/) mice exhibited increased inflammation in the heart, whereas carditis was unchanged in DBA Stat1(/) mice. These results demonstrate that inhibition of macrophage activation and responses to IFN-gamma-mediated signaling do not alter the arthritis resistance or susceptibility phenotype; however, they do affect the severity of carditis in susceptible mouse strains.

Animals↗

PubMed2006

Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns.

Microglia, the innate immune effector cells of the CNS parenchyma, express TLR that recognize conserved motifs of microorganisms referred to as pathogen-associated molecular patterns (PAMP). All TLRs identified to date, with the exception of TLR3, use a common adaptor protein, MyD88, to transduce activation signals. Recently, we reported that microglial activation in response to the Gram-positive bacterium Staphylococcus aureus was not completely attenuated following TLR2 ablation, suggesting the involvement of additional receptors. To assess the functional role of alternative TLRs in microglial responses to S. aureus and its cell wall product peptidoglycan as well as the Gram-negative PAMP LPS, we evaluated primary microglia from MyD88 knockout (KO) and wild-type mice. The induction of TNF-alpha, IL-12 p40, and MIP-2 (CXCL2) expression by S. aureus- and peptidoglycan-stimulated microglia was MyD88 dependent, as revealed by the complete inhibition of cytokine production in MyD88 KO cells. In addition, the expression of additional pattern recognition receptors, including TLR9, pentraxin-3, and lectin-like oxidized LDL receptor-1, was regulated, in part, via a MyD88-dependent manner as demonstrated by the attenuated expression of these receptors in MyD88 KO microglia. Microglial activation was only partially inhibited in LPS-stimulated MyD88 KO cells, suggesting the involvement of MyD88-independent pathways. Collectively, these findings reveal the complex mechanisms for microglia to respond to diverse bacterial pathogens, which occur via both MyD88-dependent and -independent pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Genomic mining type III secretion system effectors in Pseudomonas syringae yields new picks for all TTSS prospectors.

Many bacterial pathogens of plants and animals use a type III secretion system (TTSS) to deliver virulence effector proteins into host cells. Because effectors are heterogeneous in sequence and function, there has not been a systematic way to identify the genes encoding them in pathogen genomes, and our current inventories are probably incomplete. A pre-closure draft sequence of Pseudomonas syringae pv. tomato DC3000, a pathogen of tomato and Arabidopsis, has recently supported five complementary studies which, collectively, identify 36 TTSS-secreted proteins and many more candidate effectors in this strain. These studies demonstrate the advantages of combining experimental and computational approaches, and they yield new insights into TTSS effectors and virulence regulation in P. syringae, potential effector targeting signals in all TTSS-dependent pathogens, and strategies for finding TTSS effectors in other bacteria that have sequenced genomes.

Arabidopsis↗

PubMed2005

CD40 signaling in macrophages induces activity against an intracellular pathogen independently of gamma interferon and reactive nitrogen intermediates.

Gamma interferon (IFN-gamma) is the major inducer of classical activation of macrophages. Classically activated mouse macrophages acquire antimicrobial activity that is largely dependent on the production of reactive nitrogen intermediates. However, protection against important intracellular pathogens can take place in the absence of IFN-gamma and nitric oxide synthase 2 (NOS2). Using Toxoplasma gondii as a model, we investigated if CD40 signaling generates mouse macrophages with effector function against an intracellular pathogen despite the absence of priming with IFN-gamma and lack of production of reactive nitrogen intermediates. CD40-stimulated macrophages acquired anti-T. gondii activity that was not inhibited by a neutralizing anti-IFN-gamma monoclonal antibody but was ablated by the neutralization of tumor necrosis factor alpha (TNF-alpha). Moreover, while the induction of anti-T. gondii activity in response to CD40 stimulation was unimpaired in macrophages from IFN-gamma(-/-) mice, macrophages from TNF receptor 1/2(-/-) mice failed to respond to CD40 engagement. In contrast to IFN-gamma-lipopolysaccharide, CD40 stimulation did not induce NOS2 expression and did not trigger production of reactive nitrogen intermediates. Neither N(G)-monomethyl-l-arginine nor diphenyleneiodonium chloride affected the induction of anti-T. gondii activity in response to CD40. Finally, macrophages from NOS2(-/-) mice acquired anti-T. gondii activity in response to CD40 stimulation that was similar to that of macrophages from wild-type mice. These results demonstrate that CD40 induces the antimicrobial activity of macrophages against an intracellular pathogen despite the lack of two central features of classically activated macrophages: priming with IFN-gamma and production of reactive nitrogen intermediates.

Animals↗

PubMed2007

The use of protoplasts to study innate immune responses.

The use of plant protoplast transient expression system has facilitated the discovery and dissection of many signal transduction pathways in response to hormones, metabolites, and stresses. Recently, Arabidopsis protoplasts also have been used successfully to study plant innate immune responses triggered by pathogen-derived elicitors. Here, we describe the detailed protocols for studying innate immune responses, including cell death and early defense gene regulation activated by two types of elicitors, pathogen-associated molecular patterns and bacterial type III effectors in Arabidopsis protoplasts. This cell-based system simplifies the complex pathogen-plant interactions to pure individual signals and synchronized cell-autonomous responses. The application of this novel approach provides high temporal and spatial resolution to enhance our understanding of the distinct and overlapping signaling events in pathogen-associated molecular pattern- and bacterial type III effector-activated immune responses at the molecular and cellular level.

Arabidopsis↗

PubMed1991

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. IV. Identification of an immunodominant T cell determinant on the N-terminal end of the VP2 capsid protein in susceptible SJL/J mice.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant animal model of human multiple sclerosis. Myelin damage induced by TMEV infection appears to be immune mediated. Disease susceptibility correlates best with the temporal development of chronic, high levels of TMEV-specific, MHC class II-restricted delayed-type hypersensitivity (DTH) responses. We have proposed a model wherein these responses result in CNS demyelination via a macrophage-mediated terminal nonspecific bystander response. As virus-specific DTH responses appear to be intimately involved in the pathogenicity of CNS demyelination, it is critical to determine the specificity of these responses so that effector T cells specific for potential pathogenic epitopes can be targeted to serve as the focus of specific immunoregulatory processes. In the current study, the capsid protein specificity of the TMEV-susceptible SJL/J and TMEV-resistant C57BL/6 mouse strains was examined. DTH and Tprlf responses in both infected and immunized SJL/J mice were found to be predominantly directed toward the VP2 capsid protein, specifically to an epitope(s) contained within the N-terminal 150 amino acids of VP2. This same epitope was also found to be dominant in priming SJL/J mice for responses to challenge with intact virions. In contrast, the T cell-mediated responses of TMEV-resistant C57BL/6 mice did not show preferential reactivity towards VP2, because all three major capsid proteins (VP1, VP2, and VP3) elicited responses with essentially equal potency. The relationship of the restricted VP2 T cell epitope to predicted neutralizing antibody sites on the VP2 protein is discussed as is the potential use of this epitope for prevention and/or treatment of TMEV-induced demyelinating disease via the induction of epitope-specific tolerance.

Animals↗

PubMed1999

Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-gamma- and tumor necrosis factor (TNF)-alpha-dependent host resistance to the intracellular pathogen, Toxoplasma gondii.

Although interferon (IFN)-gamma-activated, mononuclear phagocytes are considered to be the major effectors of resistance to intracellular pathogens, it is unclear how they control the growth of microorganisms that reside in nonhemopoietic cells. Pathogens within such cells may be killed by metabolites secreted by activated macrophages or, alternatively, directly controlled by cytokine-induced microbicidal mechanisms triggered within infected nonphagocytic cells. To distinguish between these two basic mechanisms of cell-mediated immunity, reciprocal bone marrow chimeras were constructed between wild-type and IFN-gamma receptor-deficient mice and their survival assessed following infection with Toxoplasma gondii, a protozoan parasite that invades both hemopoietic and nonhemopoietic cell lineages. Resistance to acute and persistent infection was displayed only by animals in which IFN-gamma receptors were expressed in both cellular compartments. Parallel chimera experiments performed with tumor necrosis factor (TNF) receptor-deficient mice also indicated a codependence on hemopoietic and nonhemopoietic lineages for optimal control of the parasite. In contrast, in mice chimeric for inducible nitric oxide synthase (iNOS), an enzyme associated with IFN-gamma-induced macrophage microbicidal activity, expression by cells of hemopoietic origin was sufficient for host resistance. Together, these findings suggest that, in concert with bone marrow-derived effectors, nonhemopoietic cells can directly mediate, in the absence of endogenous iNOS, IFN-gamma- and TNF-alpha-dependent host resistance to intracellular infection.

Acute Disease↗

PubMed2002

Vgamma4(+) T cells promote autoimmune CD8(+) cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4(+) Th1 cells.

T cells expressing the Vgamma4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vgamma4(+) cells. Once activated, Vgamma4(+) cells initiate myocarditis through gamma interferon (IFN-gamma)-mediated induction of CD4(+) T helper type 1 (Th1) cells in the infected animal. These CD4(+) Th1 cells are required for activation of an autoimmune CD8(+) alphabeta TCR(+) effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vgamma4(+) cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1(-/-) recipients, demonstrating the need for both infection and CD1 expression for Vgamma4(+) cell function. In contrast, CD8(+) alphabeta TCR(+) cells transfer myocarditis into either infected CD1(-/-) or uninfected recipients, showing that once activated, the CD8(+) alphabeta TCR(+) effectors function independently of both virus and CD1. Vgamma4(+) cells given to mice lacking CD4(+) T cells minimally activate the CD8(+) alphabeta TCR(+) cells. These studies show that Vgamma4(+) cells determine CVB3 pathogenicity by their ability to influence both the CD4(+) and CD8(+) adaptive immune response. Vgamma4(+) cells enhance CD4(+) Th1 (IFN-gamma(+)) cell activation through IFN-gamma- and CD1-dependent mechanisms. CD4(+) Th1 cells promote activation of the autoimmune CD8(+) alphabeta TCR(+) effectors.

Adoptive Transfer↗

PubMed2006

How to kill a mocking bug?

All metazoans have evolved means to protect themselves from threats present in the environment: injuries, viruses, fungi, bacteria and other parasites. Insect protection includes innate physical barriers and both cellular and humoral responses. The insect innate immune response, best characterized in Drosophila melanogaster, is a rapid broad response, triggered by pathogen-associated molecular patterns (PAMPs) recognition, which produces a limited range of effectors that does not alter upon continued pathogen exposure and lacks immunological memory. The Drosophila response, particularly its humoral response, has been investigated by both low and high-throughput methods. Three signalling pathways conserved between insects and mammals have been implicated in this response: Toll (equivalent to mammalian TLR), Imd (equivalent to TNFalpha) and Hop (equivalent to JAK/STAT). This review provides an entry point to the insect immune system literature outlining the main themes in D. melanogaster bacterial pathogen detection and humoral and cellular immune responses. The Drosophila immune response is compared with other insects and the mammalian immune system.

Animals↗