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PubMed2006

Presence/absence polymorphism for alternative pathogenicity islands in Pseudomonas viridiflava, a pathogen of Arabidopsis.

The contribution of arms race dynamics to plant-pathogen coevolution has been called into question by the presence of balanced polymorphisms in resistance genes of Arabidopsis thaliana, but less is known about the pathogen side of the interaction. Here we investigate structural polymorphism in pathogenicity islands (PAIs) in Pseudomonas viridiflava, a prevalent bacterial pathogen of A. thaliana. PAIs encode the type III secretion system along with its effectors and are essential for pathogen recognition in plants. P. viridiflava harbors two structurally distinct and highly diverged PAI paralogs (T- and S-PAI) that are integrated in different chromosome locations in the P. viridiflava genome. Both PAIs are segregating as presence/absence polymorphisms such that only one PAI ([T-PAI, nablaS-PAI] and [nablaT-PAI, S-PAI]) is present in any individual cell. A worldwide population survey identified no isolate with neither or both PAI. T-PAI and S-PAI genotypes exhibit virulence differences and a host-specificity tradeoff. Orthologs of each PAI can be found in conserved syntenic locations in other Pseudomonas species, indicating vertical phylogenetic transmission in this genus. Molecular evolutionary analysis of PAI sequences also argues against "recent" horizontal transfer. Spikes in nucleotide divergence in flanking regions of PAI and nabla-PAI alleles suggest that the dual PAI polymorphism has been maintained in this species under some form of balancing selection. Virulence differences and host specificities are hypothesized to be responsible for the maintenance of the dual PAI system in this bacterial pathogen.

Arabidopsis↗

PubMed2004

Effector genes of Xanthomonas axonopodis pv. vesicatoria promote transmission and enhance other fitness traits in the field.

Establishing durable disease resistance in agricultural crops, where much of the plant defense is provided through effector-R gene interactions, is complicated by the ability of pathogens to overcome R gene resistance by losing the corresponding effector gene. Many proposed methods to maintain disease resistance in the field depend on the idea that effector gene loss results in a fitness cost to the pathogen. In this article we test for fitness costs of effector gene function loss. We created directed knockouts of up to four effector genes from the bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria (Xav) and examined the effect of the loss of a functional gene product on several important fitness parameters in the field. These traits included transmission, lesion development, and epiphytic survival. We found that the products of all four effector genes had significant and often additive effects on fitness traits. Additional greenhouse tests revealed costs of effector gene loss on in planta growth and further showed that the effects on lesion development were separable from the effects on growth. Observable fitness effects of the three plasmid-borne effector genes were dependent upon the loss of functional avrBs2, indicating that complex functional interactions exist among effector genes with Xav.

Analysis of Variance↗

PubMed2004

Evolution of the innate immune system: the worm perspective.

Simple model organisms that are amenable to comprehensive experimental analysis can be used to elucidate the molecular genetic architecture of complex traits. They can thereby enhance our understanding of these traits in other organisms, including humans. Here, we describe the use of the nematode Caenorhabditis elegans as a tractable model system to study innate immunity. We detail our current understanding of the worm's immune system, which seems to be characterized by four main signaling cascades: a p38 mitogen-activated protein kinase, a transforming growth factor-beta-like, a programed cell death, and an insulin-like receptor pathway. Many details, especially regarding pathogen recognition and immune effectors, are only poorly characterized and clearly warrant further investigation. We additionally speculate on the evolution of the C. elegans immune system, taking into special consideration the relationship between immunity, stress responses and digestion, the diversification of the different parts of the immune system in response to multiple and/or coevolving pathogens, and the trade-off between immunity and host life history traits. Using C. elegans to address these different facets of host-pathogen interactions provides a fresh perspective on our understanding of the structure and complexity of innate immune systems in animals and plants.

Amino Acid Sequence↗

PubMed2003

Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils.

Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against bacterial pathogens. Recent evidence suggests that PMN apoptosis facilitates resolution of inflammation during bacterial infection. Although progress has been made toward understanding apoptosis in neutrophils, very little is known about transcriptional regulation of this process during bacterial infection. To gain insight into the molecular processes that facilitate resolution of infection, we measured global changes in PMN gene expression during phagocytosis of a diverse group of bacterial pathogens. Genes encoding key effectors of apoptosis were up-regulated, and receptors critical to innate immune function were down-regulated during apoptosis induced by phagocytosis of Burkholderia cepacia, Borrelia hermsii, Listeria monocytogenes, Staphylococcus aureus, and Streptococcus pyogenes. Importantly, we identified genes that comprise a common apoptosis differentiation program in human PMNs after phagocytosis of pathogenic bacteria. Unexpectedly, phagocytosis of Str. pyogenes induced changes in neutrophil gene expression not observed with other pathogens tested, including down-regulation of 21 genes involved in responses to IFN. Compared with other bacteria, PMN apoptosis was significantly accelerated by Str. pyogenes and was followed by necrosis. Thus, we hypothesize that there are two fundamental outcomes for the interaction of bacterial pathogens with neutrophils: (i) phagocytosis of bacteria induces an apoptosis differentiation program in human PMNs that contributes to resolution of bacterial infection, or (ii) phagocytosis of microorganisms such as Str. pyogenes alters the apoptosis differentiation program in neutrophils, resulting in pathogen survival and disease.

Apoptosis↗

PubMed2005

Trafficking arms: oomycete effectors enter host plant cells.

Oomycetes cause devastating plant diseases of global importance, yet little is known about the molecular basis of their pathogenicity. Recently, the first oomycete effector genes with cultivar-specific avirulence (AVR) functions were identified. Evidence of diversifying selection in these genes and their cognate plant host resistance genes suggests a molecular "arms race" as plants and oomycetes attempt to achieve and evade detection, respectively. AVR proteins from Hyaloperonospora parasitica and Phytophthora infestans are detected in the plant host cytoplasm, consistent with the hypothesis that oomycetes, as is the case with bacteria and fungi, actively deliver effectors inside host cells. The RXLR amino acid motif, which is present in these AVR proteins and other secreted oomycete proteins, is similar to a host-cell-targeting signal in virulence proteins of malaria parasites (Plasmodium species), suggesting a conserved role in pathogenicity.

Algal Proteins↗

PubMed2003

Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma.

Bronchial asthma is characterized by massive infiltration of eosinophils and airway hyperreactivity (AHR), which are caused by overproduction of Th2 cytokines (IL-4, IL-5, and IL-13) by allergen-specific T cells. We recently demonstrated a critical contribution of OX40 ligand (OX40L) to the development of Th2-mediated experimental leishmaniasis. In this study, we have examined the role of OX40L in the development of Th2-mediated pulmonary inflammation by utilizing OX40L-deficient mice and a neutralizing anti-OX40L mAb in a murine model of asthma. Sensitization and airway challenge with ovalbumin in wild-type BALB/c mice induced a typical allergic asthma characterized by AHR, accumulation of eosinophils, increased mucus production, and high levels of Th2 cytokines in the lung. All these asthmatic responses were not induced in OX40L-deficient BALB/c mice. Administration of neutralizing anti-OX40L mAb in wild-type BALB/c mice during the sensitization period also abolished the induction of asthmatic responses. In contrast, administration of anti-OX40L mAb during the challenge period did not inhibit the asthmatic responses. These results indicate a critical role for OX40L in the induction phase, which leads to the development of pathogenic Th2 cells, but not in the effector phase, which includes migration and activation of pathogenic Th2 cells in the lung.

Animals↗

PubMed2000

Characterization of T cell receptor associated with the development of P2 peptide-induced autoimmune neuritis.

To characterize experimental autoimmune neuritis (EAN)-inducing T cells in more detail, we performed CDR3 spectratyping analysis and found oligoclonal expansion of several Vbeta spectratypes in nerve-infiltrating T cells. Vbeta5 expansion was observed all the stages examined, whereas Vbeta8.2 and Vbeta17 expansion was mainly found at the peak and preclinical stages, respectively. Since Vbeta5 expansion persists throughout the course of the disease, Vbeta5+ T cells are judged to be the main effector cells. Vbeta8.2+ and Vbeta17+ T cells may also be pathogenic but are not the main effectors because expansion of these spectratypes was found at a limited period of time. Sequence analysis revealed that Vbeta5, Vbeta8.2 and Vbeta17 spectratype-derived TCR clones possess their own dominant sequences in the CDR3 region with no homology among the clones. These findings suggest that polyclonally activated T cells are involved in the formation of the nerve lesion. Furthermore, vaccination with Vbeta5 DNA, but not with Vbeta10 DNA, suppressed the development of EAN significantly. Collectively, these findings indicate that determination of autoimmune disease-associated TCR by CDR3 spectratyping provides useful information for designing TCR-based immunotherapy for the disease.

Amino Acid Sequence↗

PubMed2005

Qualitatively distinct patterns of cytokines are released by human dendritic cells in response to different pathogens.

Dendritic cells produce cytokines that regulate the class of the adaptive immune response. Microbial recognition is mediated, at least in part, by pattern recognition receptors such as Toll-like receptors, which influence dendritic cell maturation. In humans it is not yet clear how intact pathogens modulate the developing immune response. To address the effects of intact pathogens on the maturation and effector functions of human dendritic cells, we investigated their responses to a number of microbial pathogens. We studied a range of micro-organisms including Gram-negative bacteria (Escherichia coli and Salmonella enterica sv. typhimurium), Gram-positive cocci (Staphylococcus aureus) and atypical bacteria (Mycobacterium tuberculosis and Mycoplasma hominis) as well as the human protozoal parasite Trichomonas vaginalis. The micro-organisms were fixed in formaldehyde to prevent replication whilst preserving surface morphology. All the pathogens induced similar up-regulation of dendritic cell activation-associated cell surface markers but there was a profound difference in the patterns of cytokines produced by the stimulated dendritic cells. Some pathogens (E. coli, Salmonella enterica sv. typhimurium and S. aureus) induced interleukin-12 (IL-12), IL-10 and interferon-alpha whereas others (M. tuberculosis, Mycoplasma hominis and T. vaginalis) induced only IL-10. This differential effect was not altered by costimulation of the dendritic cells through CD40. These results support the notion that human dendritic cells are plastic in their response to microbial stimuli and that the nature of the pathogen dictates the response of the dendritic cell.

Animals↗

PubMed2004

Effective targeting of pathogens to neutrophils via chimeric surfactant protein D/anti-CD89 protein.

Targeting of specific pathogens to FcRs on immune effector cells by using bispecific Abs was reported to result in effective killing of the pathogens, both in vitro and in vivo. Instead of targeting a specific pathogen to an FcR, we assessed whether a broad spectrum of pathogens can be targeted to an FcR using surfactant protein D (SP-D). SP-D is a collectin that binds a great variety of pathogens via its carbohydrate recognition domain. A recombinant trimeric fragment of SP-D (rfSP-D), consisting of the carbohydrate recognition domain and neck domain of human SP-D, was chemically cross-linked to the Fab' of an Ab directed against the human Fc alpha RI (CD89). In vitro, the chimeric rfSP-D/anti-CD89 protein enhanced uptake of Escherichia coli, Candida albicans, and influenza A virus by human neutrophils. Blocking of the interaction between rfSP-D/anti-CD89 and either the pathogen or CD89 abolished its stimulatory effect on pathogen uptake by neutrophils. In addition, rfSP-D/anti-CD89 stimulated killing of E. coli and C. albicans by neutrophils and enhanced neutrophil activation by influenza A virus. In conclusion, rfSP-D/anti-CD89 effectively targeted three structurally unrelated pathogens to neutrophils. (Col)lectin-based chimeric proteins may thus offer promise for therapy of infectious disease.

Animals↗

PubMed2006

Adaptation of Legionella pneumophila to the host environment: role of protein secretion, effectors and eukaryotic-like proteins.

The intracellular pathogen Legionella pneumophila has evolved sophisticated mechanisms that enable it to subvert host functions, enter, survive and replicate in amoebae or alveolar macrophages, and to finally evade these hosts. Protozoa are essential for the growth of Legionella and the interaction with amoeba seems to be the driving force in the evolution of its pathogenicity. This is reflected in the genome of this pathogen, which encodes a high number and variety of eukaryotic-like proteins that are able to interfere in the various steps of the infectious cycle by mimicking functions of eukaryotic proteins. Central to the pathogenicity of L. pneumophila are the many secretion systems delivering these and other effectors to the host cell. Recent studies have highlighted the multi-functional role of these factors secreted by L. pneumophila, in host-pathogen interactions.

Adaptation, Physiological↗

PubMed2000

Pseudomonas syringae Hrp type III secretion system and effector proteins.

Pseudomonas syringae is a member of an important group of Gram-negative bacterial pathogens of plants and animals that depend on a type III secretion system to inject virulence effector proteins into host cells. In P. syringae, hrp/hrc genes encode the Hrp (type III secretion) system, and avirulence (avr) and Hrp-dependent outer protein (hop) genes encode effector proteins. The hrp/hrc genes of P. syringae pv syringae 61, P. syringae pv syringae B728a, and P. syringae pv tomato DC3000 are flanked by an exchangeable effector locus and a conserved effector locus in a tripartite mosaic Hrp pathogenicity island (Pai) that is linked to a tRNA(Leu) gene found also in Pseudomonas aeruginosa but without linkage to Hrp system genes. Cosmid pHIR11 carries a portion of the strain 61 Hrp pathogenicity island that is sufficient to direct Escherichia coli and Pseudomonas fluorescens to inject HopPsyA into tobacco cells, thereby eliciting a hypersensitive response normally triggered only by plant pathogens. Large deletions in strain DC3000 revealed that the conserved effector locus is essential for pathogenicity but the exchangeable effector locus has only a minor role in growth in tomato. P. syringae secretes HopPsyA and AvrPto in culture in a Hrp-dependent manner at pH and temperature conditions associated with pathogenesis. AvrPto is also secreted by Yersinia enterocolitica. The secretion of AvrPto depends on the first 15 codons, which are also sufficient to direct the secretion of an Npt reporter from Y. enterocolitica, indicating that a universal targeting signal is recognized by the type III secretion systems of both plant and animal pathogens.

Bacterial Proteins↗

PubMed2001

The meandering 45-year odyssey of a clinical immunologist.

My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.

Allergy and Immunology↗

PubMed2006

Recognition and signaling by toll-like receptors.

Toll-like receptors (TLRs) are transmembrane proteins that detect invading pathogens by binding conserved, microbially derived molecules and that induce signaling cascades for proinflammatory gene expression. A critical component of the innate immune system, TLRs utilize leucine-rich-repeat motifs for ligand binding and a shared cytoplasmic domain to recruit the adaptors MyD88, TRIF, TIRAP, and/or TRAM for downstream signaling. Despite significant domain conservation, TLRs induce gene programs that lead not only to the robust production of general proinflammatory mediators but also to the production of unique effectors, which provide pathogen-tailored immune responses. Here we review the mechanisms by which TLRs recognize pathogens and induce distinct signaling cascades.

Animals↗

PubMed2002

The ShcA protein is a molecular chaperone that assists in the secretion of the HopPsyA effector from the type III (Hrp) protein secretion system of Pseudomonas syringae.

Pseudomonas syringae uses a type III protein secretion system encoded by the Hrp pathogenicity island (Pai) to translocate effector proteins into plant cells. One of these effector proteins is HopPsyA. A small open reading frame (ORF), named shcA, precedes the hopPsyA gene in the Hrp Pai of P. s. syringae 61. The predicted amino acid sequence of shcA shares general characteristics with chaperones used in type III protein secretion systems of animal pathogens. A functionally non-polar deletion of shcA in P. s. syringae 61 resulted in the loss of detectable HopPsyA in supernatant fractions, consistent with ShcA acting as a chaperone for HopPsyA. Cosmid pHIR11 carries a functional set of type III genes from P. s. syringae 61 and confers upon saprophytes the ability to secrete HopPsyA in culture and to elicit a HopPsyA-dependent hypersensitive response (HR) on tobacco. P. fluorescens carrying a pHIR11 derivative lacking shcA failed to secrete HopPsyA in culture, but maintained the ability to secrete another type III-secreted protein, HrpZ. This pHIR11 derivative was also greatly reduced in its ability to elicit an HR, indicating that the ability to translocate HopPsyA into plant cells was compromised. Using affinity chromatography, we showed that ShcA binds directly to HopPsyA and that the ShcA binding site must reside within the first 166 amino acids of HopPsyA. Thus, ShcA represents the first demonstrated chaperone used in a type III secretion system of a bacterial plant pathogen. We searched known P. syringae type III-related genes for neighbouring ORFs that shared the general characteristics of type III chaperones and identified five additional candidate type III chaperones. Therefore, it is likely that chaperones are as prevalent in bacterial plant pathogen type III systems as they are in their animal pathogenic counterparts.

Bacterial Proteins↗

PubMed2004

Distribution of espI among clinical enterohaemorrhagic and enteropathogenic Escherichia coli isolates.

Enterohaemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli are important diarrhoeagenic pathogens; infection is dependent on translocation of a number of type III effector proteins. Until recently all the known effectors were encoded on the LEE pathogenicity island, which also encodes the adhesin intimin and the type III secretion apparatus. Recently, a novel non-LEE effector protein, EspI/NleA, which is required for full virulence in vivo and is encoded on a prophage, was identified. The aim of this study was to determine the distribution of espI among clinical EHEC and EPEC isolates. espI was detected in 86 % and 53 % of LEE+ EHEC and EPEC strains, respectively. Moreover, the espI gene was more commonly found in patients suffering from a more severe disease.

Adhesins, Bacterial↗

PubMed2005

Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion.

We tracked pathogenic myelin basic protein-specific CD4+ effector T cells in early central nervous system (CNS) lesions of experimental autoimmune encephalomyelitis (EAE) by combining two-photon imaging and fluorescence video microscopy. We made two key observations: (a) the majority of the cells (65%) moved fast (maximal speed 25 microm/min) and apparently nondirected through the compact tissue; and (b) a second group of effector T cells (35%) appeared tethered to a fixed point. Polarization of T cell receptor and adhesion molecules (lymphocyte function-associated antigen 1) towards this fixed point suggests the formation of immune synapses. Nonpathogenic, ovalbumin-specific T cells were not tethered in the CNS and did not form synapse-like contacts, but moved through the tissue. After intrathecal injection of antigen, 40% of ovalbumin-specific T cells became tethered. Conversely, injection of anti-major histocompatibility complex class II antibodies profoundly reduced the number of stationary pathogenic T cells within the CNS (to 15%). We propose that rapid penetration of the CNS parenchyma by numerous autoimmune effector T cells along with multiple autoantigen-presentation events are responsible for the fulminate development of clinical EAE.

Animals↗

PubMed2024

A gene with a thousand alleles: The hyper-variable effectors of plant-parasitic nematodes.

Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and highly mutable gene families. Even in this context, we discovered unprecedented variation in the hyper-variable (HYP) effectors of plant-parasitic nematodes. HYP effectors are single-gene loci that potentially harbor thousands of alleles. Alleles vary in the organization, as well as the number, of motifs within a central hyper-variable domain (HVD). We dramatically expand the HYP repertoire of two plant-parasitic nematodes and define distinct species-specific "rules" underlying the apparently flawless genetic rearrangements. Finally, by analyzing the HYPs in 68 individual nematodes, we unexpectedly found that despite the huge number of alleles, most individuals are germline homozygous. These data support a mechanism of programmed genetic variation, termed HVD editing, where alterations are locus specific, strictly governed by rules, and theoretically produce thousands of variants without errors.

Animals↗

PubMed2005

Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.

CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

Animals↗