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PubMedDate not supplied

Inhibition of maturation of human monocyte-derived dendritic cells in a patient with Mycobacterium avium infection.

Mycobacterium avium complex is a facultative intracellular pathogen that can cause pulmonary disease in immunocompromised individuals. Dendritic cells (DCs) play a central role in protective immunity against mycobacteria. Mycobacterium avium complex infects DCs but does not impair in vitro infected monocytes differentiation into DCs. A 54-year old woman affected by chronic graft-versus-host-disease (cGVHD) was referred to our Division of Dermatology. Immature DCs were generated from her monocytes. One week later she was hospitalized due to a lung infection with Mycobacterium avium complex. Monocyte-derived DCs during Mycobacterium avium infection expressed low levels of CD1a and CD80 as determined by flow cytometry. They also expressed high levels of CD83 and CD86, and when stimulated with LPS for 24 hrs they slightly up-regulated CD83 and did not produce IL12. When monocyte-derived DCs were obtained from the patient after having recovered from the Mycobacterium avium complex infection, they expressed normal levels of CD1a and CD80 and were negative both for CD83 and for CD86. IL12 production in response to LPS was restored. Inhibition of DC maturation by the in vivo infection with Mycobacterium avium may be an immune-evasion mechanism used by the pathogen because incompletely matured DCs may not activate effector T cells efficiently in vivo.

Antigens, CD↗

PubMed2005

Application of vaccine technology to prevention of Pseudomonas aeruginosa infections.

Development of an effective vaccine against the multiple presentations of Pseudomonas aeruginosa infection, including nosocomial pneumonia, bloodstream infections, chronic lung infections in cystic fibrosis patients and potentially sight-threatening keratitis in users of contact lenses, is a high priority. As with vaccine development for any pathogen, key information about the most effective immunologic effectors of immunity and target antigens needs to be established. For P. aeruginosa, although there is a role for cell-mediated immunity in animals following active vaccination, the bulk of the data indicate that opsonically-active antibodies provide the most effective mediators of acquired immunity. Major target antigens include the lipopolysaccharide O-polysaccharides, cell-surface alginate, flagella, components of the Type III secretion apparatus and outer membrane proteins with a potentially additive effect achieved by including immune effectors to toxins and proteases. A variety of active vaccination approaches have the potential for efficacy such as vaccination with purified or recombinant antigens incorporating multiple epitopes, conjugate vaccines incorporating proteins and carbohydrate antigens, and live attenuated vaccines, including heterologous antigen delivery systems expressing immunogenic P. aeruginosa antigens. A diverse range of passive immunotherapeutic approaches are also candidates for effective immunity, with a variety of human monoclonal antibodies described over the years with good preclinical efficacy and some early Phase I and II studies in humans. Finding an effective active and/or passive vaccination strategy for P. aeruginosa infections could be realized in the next 5 to 10 years, but will require that advances are made in the understanding of antigen expression and immune effectors that work in different human tissues and clinical settings, and also require a means to validate that clinical outcomes achieved in Phase III trials represent meaningful advances in management and treatment of P. aeruginosa infections.

Animals↗

PubMed1999

Activated lymphocytes promote endothelial cell detachment from matrix: a role for modulation of endothelial cell beta 1 integrin affinity.

In vivo, MHC class I-restricted injury of allogeneic tissue or cells infected by intracellular pathogens occurs in the absence of classical cytolytic effector mechanisms and Ab. Modulation of the target cell adhesion to matrix may be an additional mechanism used to injure vascular or epithelial cells in inflammation. We studied the mechanisms of human umbilical vein endothelial cell (EC) detachment from matrix-coated plastic following contact by concanamycin A-treated lymphocytes as an in vitro model of perforin-independent modulation of EC basement membrane adhesion. Human PBL were depleted of monocytes, stimulated, then added to an EC monolayer plated on either fibronectin or type I collagen matrices. Activated, but not resting, PBL induced progressive EC detachment from the underlying matrix. Injury of the EC monolayer required direct cell contact with the activated lymphocytes because no detachment was seen when the PBL were placed above a Transwell membrane. Moreover plasma membranes prepared from activated but not resting PBL induced EC detachment. Adherent EC stimulated with activated PBL did not show evidence of apoptosis using TUNEL and annexin V staining at time points before EC detachment was observed. Finally, neither the matrix metalloproteinase inhibitors o-phenanthroline and BB-94 nor aprotinin blocked EC detachment. However, activation of EC beta1 integrin using mAb TS2/16 or Mg2+ decreased EC detachment. These data indicate that cell-cell contact between activated PBL and EC reduces adhesion of EC to the underlying matrix, at least in part by inducing changes in the affinity of the endothelial beta 1 integrin.

Adjuvants, Immunologic↗

PubMed2005

Iron overload and tuberculosis: a case for iron chelation therapy.

Elevated levels of iron impair immune defence mechanisms, and specifically the macrophage function of innate immunity. Iron enhances Mycobacterium tuberculosis infection, M. tuberculosis replication, progression to clinical disease and death from tuberculosis (TB). Chelation of iron in individuals with an excessive iron burden may reduce M. tuberculosis viability and replication, restore host defence mechanisms and could find application in the prevention and treatment strategies in settings where both iron overload and TB are prevalent. The objective of this paper was to summarise recent literature on the role of iron in TB pathogenesis and to examine the potential of iron chelation therapy. The literature confirms a key role for iron in mycobacterial virulence. The ability of chelation to enhance host effector mechanisms and to inhibit replication of various pathogens justifies further studies into iron chelation as a potential additive therapy for TB.

Chelating Agents↗

PubMed1987

Inability of recombinant interferon-gamma to activate the antibacterial activity of mouse peritoneal macrophages against Listeria monocytogenes and Salmonella typhimurium.

The effect of recombinant murine interferon-gamma (rIFN-gamma) as single stimulus for the activation of antibacterial activity of macrophages was investigated on the basis of the rate of intracellular killing of Listeria monocytogenes and Salmonella typhimurium by normal and rIFN gamma-activated peritoneal macrophages of CBA and C57BL/10 mice, which differ in natural resistance to infection by these bacteria. Eighteen hours after i.p. injection of 10 to 1 X 10(4) U rIFN-gamma, resident and exudate peritoneal macrophages which had phagocytosed L. monocytogenes or S. typhimurium in vivo, killed both species in vitro just as efficiently as did resident macrophages of normal mice. Similar results were obtained after 18 hr of in vitro incubation of resident or exudate peritoneal macrophages with 0.1 to 1 X 10(4) U/ml rIFN-gamma. Consistent with the in vitro findings, two i.v. injections of 5 X 10(4) U rIFN-gamma did not affect the rate of in vivo proliferation of L. monocytogenes or S. typhimurium in the spleens of mice during the first 2 days after i.v. injection of the bacteria. Compared with the effect on the controls, two i.p. injections of 5 X 10(2) to 5 X 10(4) U rIFN-gamma did not decrease the numbers of viable S. typhimurium in either the peritoneal cell suspension or the spleen 24 hr after i.p. injection of the bacteria. Checking the state of activation of rIFN-gamma-activated macrophages on the basis of two commonly used criteria for macrophage activation showed that rIFN-gamma-activated macrophages inhibited the intracellular replication of Toxoplasma gondii and displayed enhanced O2 consumption and H2O2 release after stimulation with phorbol myristate acetate compared with macrophages from normal CBA and C57BL/10 mice. The present findings show that as single activating stimulus, rIFN-gamma is not capable of activating the antibacterial effector functions of peritoneal macrophages against facultative intracellular pathogens such as L. monocytogenes and S. typhimurium.

Animals↗

PubMed1988

T-cell differentiation and effector functions.

T cells and their subpopulations have many different functions important for (i) the regulation of immune responses through the release of antigen non-specific lymphokines and (ii) as effector cells to rid the host of intracellular pathogens, be they bacteria, parasites or viruses. In this short summary only a few features of T-cell function can be summarized, and studies in virus infection will serve as illustrations.

Animals↗

PubMed2002

Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappa B pathway.

Secreted prokaryotic effector proteins have evolved to modulate the cellular functions of specific eukaryotic hosts. Generally, these proteins are considered virulence factors that facilitate parasitism. However, in certain plant and insect eukaryotic/prokaryotic relationships, effector proteins are involved in the establishment of commensal or symbiotic interactions. In this study, we report that the AvrA protein from Salmonella typhimurium, a common enteropathogen of humans, is an effector molecule that inhibits activation of the key proinflammatory NF-kappaB transcription factor and augments apoptosis in human epithelial cells. This activity is similar but mechanistically distinct from that described for YopJ, an AvrA homolog expressed by the bacterial pathogen Yersinia. We suggest that AvrA may limit virulence in vertebrates in a manner analogous to avirulence factors in plants, and as such, is the first bacterial effector from a mammalian pathogen that has been ascribed such a function.

Apoptosis↗

PubMed2004

CpG oligodeoxynucleotide induction of antiviral effector molecules in sheep.

Immunostimulatory CpG oligodeoxynucleotide (ODN) can protect mice against infection by many pathogens but the mechanisms mediating disease protection are not well defined. Furthermore, the mechanisms of CpG ODN induced disease protection in vivo have not been investigated in other species. We investigated the induction of antiviral effector molecules in sheep treated with a class B CpG ODN (2007). Subcutaneous injection of ODN 2007 induced a dose-dependent increase in serum levels of the antiviral effector molecule, 2'5'-A synthetase. Peak levels of enzyme were observed 4 days following ODN injection and enzyme levels remained elevated for the following 3-5 days. Repeated ODN injections induced a more sustained elevation of serum 2'5'-A synthetase activity. Finally, formulation of ODN 2007 in emulsigen increased the level of serum 2'5'-A synthetase activity and this response was CpG-specific. Elevated serum 2'5'-A synthetase activity suggested that CpG ODN acted through the induction of either interferon (IFN)-alpha or IFN-gamma. ODN 2007 did not induce detectable levels of IFN-alpha or IFN-gamma when incubated with peripheral blood mononuclear cells, but both IFN-alpha and IFN-gamma were detected following stimulation of lymph node cells with ODN 2007. CpG ODN induction of 2'5'-A synthetase in vitro correlated with the secretion of both IFN-alpha and IFN-gamma. Furthermore, immunohistochemical staining of skin revealed a marked cellular infiltration at the site of ODN 2007 injection. This cellular infiltration was CpG-specific and consisted of primarily CD172(+) myeloid cells. Many of the cells recruited to the site of ODN 2007 injection expressed IFN-alpha and some IFN-gamma. These observations support the conclusion that localized cell recruitment and activation contribute to CpG ODN induction of antiviral effector molecules, such as interferon and 2'5'-A synthetase.

2',5'-Oligoadenylate Synthetase↗

PubMed2006

Mutational analysis of Salmonella translocated effector members SifA and SopD2 reveals domains implicated in translocation, subcellular localization and function.

Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen causing disease in several hosts. These bacteria use two distinct type III secretion systems that inject effector proteins into the host cell for invasion and to alter maturation of the Salmonella-containing vacuole. Members of the Salmonella translocated effector (STE) family contain a conserved N-terminal translocation signal of approximately 140 aa. In this study, the STE family member SifA was examined using deletion strategies. Small deletions (approx. 20 residues long) throughout SifA were sufficient to block its secretion and/or translocation into host cells. Transfection of HeLa cells with a GFP-SifA fusion was previously shown to be sufficient to induce formation of Sif-like tubules resembling structures present in Salmonella-infected cells. The present study showed that both N- and C-terminal domains of SifA are required for this phenotype. Furthermore, both domains could induce aggregation of Lamp1-positive compartments, provided they were coupled to the minimal C-terminal membrane-anchoring motif of SifA. Mutation or deletion of the conserved STE N-terminal WEK(I/M)xxFF translocation motif of SopD2 disrupted its association with Lamp1-positive compartments, implicating these residues in both effector translocation and subcellular localization. Interestingly, one GFP-SifA deletion mutant lacking residues 42-101, but retaining the WEK(I/M)xxFF motif, targeted the Golgi apparatus. In addition, short peptides containing the signature WEK(I/M)xxFF motif derived from the N-termini of Salmonella effectors SopD2, SseJ and SspH2 were sufficient to localize GFP to the Golgi. These studies suggest that Salmonella effectors contain multifunctional motifs or domains that regulate several effector traits, including protein secretion/translocation, localization and subversion of host cell systems. Conditions that perturb the tertiary structure of effectors can influence their localization in host cells by liberating cryptic intracellular targeting motifs.

Amino Acid Motifs↗

PubMed2005

Structural characterization of the molecular platform for type III secretion system assembly.

Type III secretion systems (TTSSs) are multi-protein macromolecular 'machines' that have a central function in the virulence of many Gram-negative pathogens by directly mediating the secretion and translocation of bacterial proteins (termed effectors) into the cytoplasm of eukaryotic cells. Most of the 20 unique structural components constituting this secretion apparatus are highly conserved among animal and plant pathogens and are also evolutionarily related to proteins in the flagellar-specific export system. Recent electron microscopy experiments have revealed the gross 'needle-shaped' morphology of the TTSS, yet a detailed understanding of the structural characteristics and organization of these protein components within the bacterial membranes is lacking. Here we report the 1.8-A crystal structure of EscJ from enteropathogenic Escherichia coli (EPEC), a member of the YscJ/PrgK family whose oligomerization represents one of the earliest events in TTSS assembly. Crystal packing analysis and molecular modelling indicate that EscJ could form a large 24-subunit 'ring' superstructure with extensive grooves, ridges and electrostatic features. Electron microscopy, labelling and mass spectrometry studies on the orthologous Salmonella typhimurium PrgK within the context of the assembled TTSS support the stoichiometry, membrane association and surface accessibility of the modelled ring. We propose that the YscJ/PrgK protein family functions as an essential molecular platform for TTSS assembly.

Amino Acid Sequence↗

PubMed1982

In vitro interactions of immune lymphocytes and Cryptococcus neoformans.

CBA/J mice immunized subcutaneously with emulsions of heat-killed Cryptococcus neoformans in complete Freund adjuvant displayed delayed-type hypersensitivity to cryptococcal culture filtrate antigen and developed sensitized splenic lymphoid cells which inhibited the growth of C. neoformans in vitro. The in vitro assay of growth inhibition served to investigate further the kinetics of the effect of sensitized lymphoid cells on the pathogen. There was a close correlation between the delayed-type hypersensitivity response in mice and inhibition of growth of C. neoformans by lymphoid cells. Sensitized splenic lymphocytes capable of inhibiting the growth of the cryptococci were detected at day 6 after immunization and reached maximum levels by days 8 through 16. Inhibition of growth was highest with effector-to-target cell ratios of 300:1 or greater. Inhibition of growth of C. neoformans by sensitized lymphoid cells was detectable as early as 4 h after effector and target cells were mixed and increased gradually, reaching a maximum at 24 h, but dropped significantly by 48 h. By supplementing the reaction mixtures with fresh medium or additional sensitized effector cells during incubation, the inhibition of growth of C. neoformans could be maintained through 48 h. C. neoformans-sensitized effector lymphoid populations not only inhibited the growth of the pathogen in vitro but also restricted C. neoformans proliferation in various vital organs upon transfer to naive recipient animals, indicating that the in vitro growth inhibition assay may be a means of assessing the resistance of animals to C. neoformans. The effector cells from sensitized animals were nylon wool-nonadherent Thy-1+ and Ia+ lymphocytes.

Animals↗

PubMed2002

Type III secretion of Salmonella enterica serovar Typhimurium translocated effectors and SseFG.

The type III secretion system (TTSS) encoded by Salmonella enterica serovar Typhimurium pathogenicity island 2 (SPI2) is employed by Salmonella enterica for interaction with host cells during the intracellular phase of pathogenesis. This TTSS secretes a set of SPI2-encoded proteins in vitro and translocates Salmonella serovar Typhimurium translocated effectors (STE) that are encoded by genes outside of SPI2 into host cells. Using an epitope-tagging approach, we analyzed secretion of proteins by the TTSS of SPI2 and identified SseF and SseG as further secreted substrate proteins. Three members of the STE family, SifA, SifB, and SseJ, were secreted under conditions that also induce secretion of SPI2-encoded substrate proteins.

Bacterial Proteins↗

PubMed2004

Genetic screening of Hrp type III-related pathogenicity genes controlled by the HrpB transcriptional activator in Ralstonia solanacearum.

As in many other Gram-negative phytopathogenic bacteria, the Hrp type III secretion system is essential for the pathogenicity of Ralstonia solanacearum on host plants. The expression of most of the type III effector genes previously isolated from R. solanacearum is co-regulated with those of hrp genes by an AraC-type transcriptional activator, HrpB. In order to isolate type III-related pathogenicity genes, we screened hrpB-regulated genes in R. solanacearum. Using a transposon-based system, we isolated 30 novel hpx (hrpB-dependent expression) genes outside the hrp gene cluster. Most of the hpx genes contain a PIP (plant-inducible promoter) box-like motif in their putative promoter regions. Seven hpx genes encoded homologues of known type III effectors and type III-related proteins found in other animal and plant pathogens. Four encoded known enzymes, namely, glyoxalase I, Nudix hydrolase, spermidine synthase and transposase. Interestingly, six hpx genes encoded two types of leucine-rich repeat (LRR) protein. Products of the remaining genes did not show any significant homology to known proteins. We also identified two novel hrpB-regulated genes, hpaZ and hpaB, downstream of hrpY in the hrp cluster. The hpaB gene of R. solanacearum, but not hpaZ, was required for both the pathogenicity and ability to induce hypersensitive reaction on plants. We show that a hpaB null mutant still produces Hrp pili on the cell surface although it shows a typical Hrp-defective phenotype on plants.

Bacterial Proteins↗

PubMed2005

Innate immune tissue injury and murine HGA: tissue injury in the murine model of granulocytic anaplasmosis relates to host innate immune response and not pathogen load.

Anaplasma phagocytophilum is an obligate intracellular tick-borne bacterium that propagates within neutrophils and causes human and animal granulocytic anaplasmosis (HGA). In the murine model of HGA, host immune response plays a more important role in histopathologic lesions than does pathogen load. We examined the role of CYBB, NOS2, and TNFalpha as effectors of innate immune-related injury. Our hypothesis is that the innate immune response to A. phagocytophilum results in inflammatory histopathology, but does not control the pathogen.

Anaplasma phagocytophilum↗

PubMed1985

Killing of yeast, germ-tube and mycelial forms of Candida albicans by murine effectors as measured by a radiolabel release microassay.

Candida albicans undergoes yeast to mycelial conversion under both in vivo and in vitro conditions but the relative pathogenicity of the two forms of growth is still unknown. By adapting a recently developed 51Cr radiolabel release assay, we have quantified the killing ability of different murine effector cell populations for the hyphal form of C. albicans. Up to 50% of specific 51Cr release from the mycelial form could be detected after incubation for only 1 h, with no requirement for opsonization, provided that appropriate effector: target cell ratios were used. The specific 51Cr release correlated well with viability, as assessed by dye exclusion tests, and with pathogenicity potential in cyclophosphamide-immunodepressed mice. Comparison of the activity of different murine effectors against yeast and hyphal forms showed that hyphal forms were killed by murine effectors to a similar, if not greater, extent than yeast forms. In particular, thioglycollate-induced murine polymorphonuclear neutrophils were able to kill hyphal cells extracellularly and without an opsonic requirement.

Animals↗

PubMed1992

Recombinant murine interferon-gamma reversibly activates rat alveolar macrophages to kill Legionella pneumophila.

The interaction of interferon (IFN)-gamma, rat alveolar macrophages, and Legionella pneumophila was studied in vitro to define the effector cell potential of alveolar macrophages against an intracellular pathogen in a model in which the efficacy of IFN-gamma could be tested in vivo. Alveolar macrophages preincubated with IFN-gamma up-regulated Ia antigen and killed 0.5-4 logs of L. pneumophila over 4 days compared with 1-2 logs of bacterial growth in untreated cells. The bactericidal effect was dose dependent, evident over a wide range of bacterial inocula, and not suppressed by hydrocortisone. Preincubation with IFN-gamma was unnecessary and insufficient, as intracellular replication was reversed by exposure to IFN-gamma up to 48 h after infection, and neutralization of IFN-gamma after infection permitted bacterial growth. IFN-gamma thus converts alveolar macrophages from target cells to effector cells in host defense against L. pneumophila and may be of therapeutic benefit in legionellosis.

Animals↗

PubMed2005

R gene expression induced by a type-III effector triggers disease resistance in rice.

Disease resistance (R) genes in plants encode products that specifically recognise incompatible pathogens and trigger a cascade of events leading to disease resistance in the host plant. R-gene specificity is dictated by both host R genes and cognate avirulence (avr) genes in pathogens. However, the basis of gene-for-gene specificity is not well understood. Here, we report the cloning of the R gene Xa27 from rice and the cognate avr gene avrXa27 from Xanthomonas oryzae pv. oryzae. Resistant and susceptible alleles of Xa27 encode identical proteins. However, expression of only the resistant allele occurs when a rice plant is challenged by bacteria harbouring avrXa27, whose product is a nuclear localized type-III effector. Induction of Xa27 occurs only in the immediate vicinity of infected tissue, whereas ectopic expression of Xa27 resulted in resistance to otherwise compatible strains of the pathogen. Thus Xa27 specificity towards incompatible pathogens involves the differential expression of the R gene in the presence of the AvrXa27 effector.

Alleles↗

PubMed1996

The role of CD40 ligand in costimulation and T-cell activation.

It is clear by now that cell-to-cell interactions involving a variety of signals are required for effective immune response. The data reviewed here suggest that CD40-CD40L interactions are critical for development of CD4 T-cell-dependent effector functions. Lack of this important interaction results in greatly reduced activation of CD4 T cells, while successful interaction of these molecules results in full activation of these T cells. Consequently, the absence of CD40-CD40L interactions leads to impairment of T-cell effector such as help for B-cell differentiation and class switch, activation of monocytes and macrophages to produce cytokines and to kill intracellular pathogens, and activation of autoreactive T cells to mount an autoimmune response. The effector functions of T cells controlled by CD40-CD40L interactions in a successful immune response are given in Table I. Data presented so far suggest that CD40-CD40L interactions play a role in early signalling events, where interactions of this kind are required to induce expression of costimulatory molecules on APC. One possible sequence of events in that APC, like DC, take up antigens at the site of injury or infection and migrate to lymph nodes, where they present antigens complexed with MHC class II molecules to naive T cells. This results in expression of CD40L on T cells. Coupling of this newly expressed CD40L on T cells with CD40 on APC results in expression of the costimulatory activity of the APC. At this time the costimulatory signal provided by the APC is received by the T cells via CD28/CTLA-4, which drives the cell to enter into cell cycle and complete T cell activation. T cells thereby activated can now enter into secondary cognate CD40-CD40L-dependent effector recognition with B cells to switch Ig class, macrophages to produce cytokines and new DC carrying the same antigen to up-regulate costimulatory activity. A tight regulation of expression of CD40L on T cells and costimulatory activity on APC would prevent activation of unwanted bystander T cells. The coupling of activation of the APC primed with the cognate antigen to the activation of the T-cell specific for that antigen in this model provides an additional regulatory step in the initiation of the immune response. This also suggests that a limited number of T cells/APC will be activated, both of which will be specific in nature. This additional step may be important for safeguarding against an autoimmune response. In addition, the fact that CD40L uniquely seems to play this role suggests that selective immunotherapies to treat autoimmune disease and prevent graft rejection can be targeted on this molecule. On the other hand, CD40-directed approaches to up-regulate costimulatory activity on APC could be developed to fight tumor growth, contain infections and treat immunodeficiencies.

Abatacept↗