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Results for “pathogen effectors”

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PubMed1990

Tumor-cytolytic human macrophages cultured as nonadherent cells: potential for the adoptive immunotherapy of cancer.

Tumor-cytolytic lymphokine (e.g., interleukin-2; IL-2)-activated killer cells are currently being evaluated in IL-2/LAK cell adoptive immunotherapy regimens for the treatment of cancer. Monocyte-derived macrophages (M phi) are also known to be efficient tumor killer cells; accordingly, M phi that have been activated in vitro may also be of therapeutic merit. However, attempts to cultivate M phi for morphological and functional studies have often been compromised because M phi adhere rapidly and tenaciously to cultureware. Studies that we have conducted to address this problem have proven successful in developing procedures for the long-term cultivation of non-adherent immunocompetent M phi in serum-free medium using petri dishes containing a thin Teflon liner. The utility of this technology is documented by the results of studies presented herein in which light and scanning electron microscopy was used to analyze tumor-cytolytic human M phi. In these experiments, we demonstrated that nonadherent immunocompetent human M phi can be prepared for detailed examinations of their pleomorphic membrane architecture. Moreover, nonadherent human M phi could readily be collected for preparing conjugates of M phi and tumor cells. It is anticipated that this technology should prove useful for future structure-function studies defining the topographical location and spatial distribution of antigens and receptors on M phi membrane ultrastructures, particularly the microvilli-like projections that bridge together an immunocompetent effector M phi and target cell (e.g., tumor cells and microbial pathogens) and which provide the physical interaction required for the initial phases of a cellular immune response that includes antigen recognition and cell-to-cell adhesion.

Cell Adhesion↗

PubMed1995

Bacillus Calmette-Guérin immunotherapy for superficial bladder cancer. New prospects for an old warhorse.

The use of live M. bovis BCG to treat superficial bladder cancer has endured its seemingly anachronistic origin in the early days of tumor immunology to emerge as the therapy of choice for superficial bladder cancer. Its superiority over conventional intravesical therapy has been established for tumor prophylaxis and treatment of residual disease and CIS, providing long-term results that have translated into improvements in disease progression and survival. Although its exact mechanism of action remains elusive, extensive studies suggest that this intracellular pathogen stimulates the immune system to produce powerful cytokine mediators and effector cells that act locally to destroy bladder tumors. Although unique toxicities occur by virtue of BCG's use as a live vaccine, this same liability has opened the door for new opportunities through the use of recombinant DNA technology. Exciting prospects include the use of BCG as a cytokine carrier and as a tumor antigen depot. Genetic engineering may also yield varients that are both intrinsically safer and more specific in bladder tumor targeting.

BCG Vaccine↗

PubMed1997

Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency.

The highly regulated secretion of effector cytokines by CD4+ T cells plays a critical role in immune protection against pathogens such as cytomegalovirus. Here, we directly compare the frequency and functional characteristics of cytomegalovirus-specific CD4+ memory/effector T cells in normal and HIV+ subjects using a novel, highly efficient multiparameter flow cytometric assay that detects the rapid intracellular accumulation of cytokine(s) after short-term (6 h) in vitro antigen stimulation. Responses in this assay correlate precisely with independent measures of sensitization history (e.g., seroreactivity), and allow the simultaneous assessment of multiple cytokines in single effector T cells. Healthy HIV- individuals manifested an average of 0.71, 0.72, 0.38, and 0.06% CD4+ T cells responding to cytomegalovirus with gamma-IFN, TNF-alpha, IL-2, and IL-4 production, respectively, with the simultaneous production of gamma-IFN, TNF-alpha, and IL-2 being the most common effector phenotype. Significantly, overall cytomegalovirus-specific CD4+ effector frequencies were markedly higher among 40% of HIV+ subjects (2.7-8.0%), and demonstrated a predominately polarized gamma-IFN+/TNF-alpha+/IL-2-/IL-4- phenotype. In contrast, CD4+ effector frequencies for heterologous, nonubiquitous viruses such as the mumps virus were low or absent in the HIV+ group. These data suggest the existence of homeostatic mechanisms in HIV disease that selectively preserve memory T cell populations reactive with ubiquitous pathogens such as cytomegalovirus-likely at the expense of T cell memory to more sporadically encountered infectious agents.

Antigens↗

PubMed1998

Functional conservation of the effector protein translocators PopB/YopB and PopD/YopD of Pseudomonas aeruginosa and Yersinia pseudotuberculosis.

Virulent Yersinia species cause systemic infections in rodents, and Y. pestis is highly pathogenic for humans. Pseudomonas aeruginosa, on the other hand, is an opportunistic pathogen, which normally infects only compromised individuals. Surprisingly, these pathogens both encode highly related contact-dependent secretion systems for the targeting of toxins into eukaryotic cells. In Yersinia, YopB and YopD direct the translocation of the secreted Yop effectors across the target cell membrane. In this study, we have analysed the function of the YopB and YopD homologues, PopB and PopD, encoded by P. aeruginosa. Expression of the pcrGVHpopBD operon in defined translocation-deficient mutants (yopB/yopD) of Yersinia resulted in complete complementation of the cell contact-dependent, YopE-induced cytotoxicity of Y. pseudotuberculosis on HeLa cells. We demonstrated that the complementation fully restored the ability of Y. pseudotuberculosis to translocate the effector molecules YopE and YopH into the HeLa cells. Similar to YopB, PopB induced a lytic effect on infected erythrocytes. The lytic activity induced by PopB could be prevented if the erythrocytes were infected in the presence of sugars larger than 3 nm in diameter, indicating that PopB induced a pore of similar size compared with that induced by YopB. Our findings show that the contact-dependent toxin-targeting mechanisms of Y. pseudotuberculosis and P. aeruginosa are conserved at the molecular level and that the translocator proteins are functionally interchangeable. Based on these similarities, we suggest that the translocation of toxins such as ExoS, ExoT and ExoU by P. aeruginosa across the eukaryotic cell membrane occurs via a pore induced by PopB.

Amino Acid Sequence↗

PubMed2005

The PhoP/PhoQ system controls the intramacrophage type three secretion system of Salmonella enterica.

Spi/Ssa is a unique type three secretion system that functions exclusively when Salmonella enterica is inside eukaryotic cells. Expression of the Spi/Ssa system and its secreted effectors is dependent on SsrB/SpiR, a two-component regulatory system encoded in the SPI-2 pathogenicity island that also harbours the spi/ssa genes. Here we determine that the PhoP/PhoQ two-component system controls the intramacrophage expression of spi/ssa genes by regulating the SsrB/SpiR system. We establish that PhoP regulates transcription of the response regulator SsrB and demonstrate binding of the PhoP protein to the ssrB promoter both in vivo using chromatin immunoprecipitation in Salmonella-infected macrophages, and in vitro using purified PhoP protein. We show that PhoP controls the SpiR sensor post-transcriptionally and identify a region in the 5' untranslated region of the spiR message that is required for this effect. The demonstration that the PhoP/PhoQ system is directly involved in the regulation of the SPI-2 pathogenicity island highlights PhoP/PhoQ's central role in Salmonella virulence. We suggest that different regulatory systems convey distinct signals over time to produce the SsrB/SpiR system, which then modulates expression of the Spi/Ssa apparatus and secreted effectors.

5' Untranslated Regions↗

PubMed2003

Anti-GM1 IgG antibodies induce leukocyte effector functions via Fcgamma receptors.

Guillain-Barré syndrome (GBS) is an immune-mediated neuropathy, in which leukocytes and humoral components of the immune system proposedly initiate localized inflammation. An important pathogenic role for anti-GM1 ganglioside antibodies has been suggested. Therefore, we evaluated anti-GM1 IgG antibody-induced leukocyte effector functions such as degranulation and phagocytosis using serum of 24 GBS patients. Serum without anti-GM1 antibodies of 9 GBS patients as well as pooled serum from healthy individuals served as controls. Ten out of 15 (67%) of anti-GM1 IgG positive sera were capable of inducing leukocyte degranulation, and 8 out of 15 (53%) of anti-GM1 IgG positive sera were capable of inducing phagocytosis of GM1-coated beads. In all of these sera anti-GM1 antibody titers were >or=1:800. No leukocyte degranulation or phagocytosis was observed in control sera. Leukocyte activation was completely abrogated in the presence of IgG receptor (FcgammaR) blocking antibodies, suggesting a crucial role for leukocyte FcgammaR in GBS pathogenesis. No correlation of antibody titers with the extent of leukocyte activation, or severity of disease was observed. These data document the capacity of anti-GM1 IgG antibodies to activate leukocyte inflammatory functions, and suggest an important role for anti-ganglioside IgG antibodies in the pathogenesis of GBS.

Adult↗

PubMed2005

Molecular basis of antigenic polymorphism of EspA filaments: development of a peptide display technology.

Like many Gram-negative pathogens, enteropathogenic (EPEC) and enterohaemorrhagic Escherichia coli (EHEC) use a macromolecular type III secretion system (TTSS) to inject effector proteins into eukaryotic host cells. The membrane-associated needle complex (NC) of the TTSS, which shows broad similarity to the flagellar basal body, is conserved amongst bacterial pathogens. However, the extracellular part of the TTSS of EPEC and EHEC is unique, in that it has a hollow, approximately 12 nm in diameter, filamentous extension to the NC. EspA filaments are homo-polymers made of the translocator protein EspA. The three-dimensional structure of EspA filaments is comparable to that of flagella; the helical symmetry and packing of the subunits forming both filamentous structures are very similar. Like flagella, EspA filaments show antigenic polymorphism as EspA from different EPEC and EHEC clones show no immunological cross-reactivity. In this study, we determined the molecular basis of the antigenic polymorphism of EspA filaments and identified a surface-exposed hypervariable domain that contains the immunodominant EspA epitope. By exchanging the hypervariable domains of EspA(EPEC) and EspA(EHEC) we swapped the antigenic specificity of the EspA filaments. As for the flagellin D3 domain, which is known to tolerate insertions of natural and artificial amino acid sequences, we have inserted short peptides into the surface-exposed, hypervariable domain of EspA. We demonstrated that the inserted peptides are presented on the surface of the recombinant EspA filaments forming a new immunodominant epitope. Accordingly, EspA filaments have a potential to be developed into a novel epitope display system.

Actins↗

PubMed2025

Avirulence depletion assay: Combining R gene-mediated selection with bulk sequencing for rapid avirulence gene identification in wheat powdery mildew.

Wheat production is threatened by multiple fungal pathogens, such as the wheat powdery mildew fungus (Blumeria graminis f. sp. tritici, Bgt). Wheat resistance breeding frequently relies on the use of resistance (R) genes that encode diverse immune receptors which detect specific avirulence (AVR) effectors and subsequently induce an immune response. While R gene cloning has accelerated recently, AVR identification in many pathogens including Bgt lags behind, preventing pathogen-informed deployment of resistance sources. Here we describe a new "avirulence depletion (AD) assay" for rapid identification of AVR genes in Bgt. This assay relies on the selection of a segregating, haploid F1 progeny population on a resistant host, followed by bulk sequencing, thereby allowing rapid avirulence candidate gene identification with high mapping resolution. In a proof-of-concept experiment we mapped the AVR component of the wheat immune receptor Pm3a to a 25 kb genomic interval in Bgt harboring a single effector, the previously described AvrPm3a2/f2. Subsequently, we applied the AD assay to map the unknown AVR effector recognized by the Pm60 immune receptor. We show that AvrPm60 is encoded by three tandemly arrayed, nearly identical effector genes that trigger an immune response upon co-expression with Pm60 and its alleles Pm60a and Pm60b. We furthermore provide evidence that Pm60 outperforms Pm60a and Pm60b through more efficient recognition of AvrPm60 effectors, suggesting it should be prioritized for wheat breeding. Finally, we show that virulence towards Pm60 is caused by simultaneous deletion of all AvrPm60 gene paralogs and that isolates lacking AvrPm60 are especially prevalent in the US thereby limiting the potential of Pm60 in this region. The AD assay is a powerful new tool for rapid and inexpensive AVR identification in Bgt with the potential to contribute to pathogen-informed breeding decisions for the use of novel R genes and regionally tailored gene deployment.

Triticum↗

PubMed2005

Activation of beta-catenin by carcinogenic Helicobacter pylori.

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag+ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is beta-catenin, and activation of beta-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates beta-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. Beta-catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag+ vs. cag- strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of beta-catenin-dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.

Adenocarcinoma↗

PubMed2003

Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way.

Mycobacteria activate a series of macrophage signalling pathways upon engaging host cell receptors and during the invasion process. These signals initiate a cascade of events leading to the production of immune effector molecules including cytokines, chemokines and reactive nitrogen intermediates. This response by the macrophage is critical for the control of the mycobacterial infection and, not surprisingly, pathogenic mycobacteria have evolved mechanisms to limit this macrophage activation. Recent data has suggested that macrophages infected with pathogenic compared to non-pathogenic mycobacteria are restricted in their activation of the mitogen activated protein kinase (MAPK) pathways. Mitogen activated protein kinase activation in macrophages appears to play an important role in promoting antimycobacterial activity and in the production of various effector molecules following a mycobacterial infection. Therefore, the ability of pathogenic mycobacteria to limit MAPK activity is likely an important virulence mechanism and may be a potential therapeutic target.

Animals↗

PubMed1979

Do natural killer cells engage in regulated reactions against self to ensure homeostasis?

Host reactivities not requiring immunization in the mouse, especially natural resistance of irradiated animals to accept grafts of normal or malignant hemopoietic cells, were compared with NK activity against the YAC-1 lymphoma. The effects of several independent variables known to influence natural resistance in vivo had a similar effect on the NK system. Figure 12 lists an impressive array of shared properties and positive correlations. In contrast, the distinctions were few and minor. Many of the positive correlations were of particular significance since the experimental variables either have opposing or no effects on conventional induced immunity. The multiplicity and pervasiveness of these correlations suggest that the cellular mechanisms underlying natural reactivities are similar or common. Cytotoxic effectors mediating natural resistance to normal cells, tumors, and cells infected with intracellular pathogens may be distinct in terms of target selectivity, yet belong to a single cell lineage subject to common regulatory influences for differentiation and function. Regulation of reactivity via suppressor cells was studied in the NK system only. The spleens of mice selected for low levels of NK activity (resulting from young age, irradiation, and treatment with the macrophage-active agents l-carrageenan or hydrocortisone acetate) contained cells capable of inhibiting the lytic function of NK effectors taken from untreated adult donors. All the suppressor cells studied were thymus-independent, as judged by their occurrence in spleens of genetically athymic mice; the suppressive function was resistant to 2000 rads of gamma-rays administered in vitro and was not restricted by the major histocompatibility complex, without exception. However, two major classes of suppressors were identified: (a) macrophagelike cells inducible by l-carrageenan or hydrocortisone acetate, and (b) nonadherent cells found in spleens of untreated infants and of irradiated adult mice. It is proposed that the suppression of NK cytolysis demonstrated in vitro was a manifestation of regulatory mechanisms modulating the level of NK activity in vivo. Macrophagelike cells that are induced, activated, or inactivated by bacteria, viruses, hormones, and other agents may act as regulators of differentiation, maturation, and function of cells belonging to the NK lineage. Nonadherent cells could be either a distinct class of suppressors or immature NK cells capable of binding but not lysing target cells. In the latter case, regulation would be achieved via competitive binding of targets by pre-NK cells presumably in dynamic equilibrium with functional (i.e. matured) NK effectors.

Animals↗

PubMed2001

Effector mechanisms of protection against Pseudomonas aeruginosa keratitis in immunized rats.

Pseudomonas aeruginosa is an opportunistic pathogen which causes sight-threatening corneal infections in humans. The purpose of this study was to evaluate various immunization routes that may provide protection against Pseudomonas keratitis and to define the molecular mechanisms involved in the protection. Sprague-Dawley rats (10 to 12 weeks old) were immunized using paraformaldehyde-killed P. aeruginosa (strain 6206) via oral, nasal, and intra-Peyer's patch (IPP) routes followed by an ocular topical booster dose. Scratched corneas were challenged with an infective dose of P. aeruginosa. Following clinical examination, eyes were enucleated for histology, polymorphonuclear leukocyte (PMN) quantitation, bacterial count, enzyme-linked immunosorbent assay, and RNase protection assay. PMN infiltration was higher early (4 h) during the infection in immunized rats than in nonimmunized rats. Later during the infection, the number of PMNs diminished in immunized rats while in nonimmunized animals the number of PMNs continued to increase. Bacteria were cleared much faster from immunized groups than from the nonimmunized group, and the nasally immunized group had the most efficacious response among the immunized groups. Nasal and IPP immunization groups had increased cytokine expression of interleukin-2 (IL-2) and IL-5 and differed from each other for IL-6. All three immunized groups had significantly reduced IL-1 beta levels when compared with the nonimmunized rats and a significantly altered profile for CINC-1 expression. This study has shown that the route of immunization modulates the inflammatory response to ocular P. aeruginosa infection, thus affecting the severity of keratitis and adverse pathology, with nasal immunization being the most effective.

Administration, Intranasal↗

PubMed2003

A pseudomonas syringae pv. tomato DC3000 Hrp (Type III secretion) deletion mutant expressing the Hrp system of bean pathogen P. syringae pv. syringae 61 retains normal host specificity for tomato.

The plant pathogenic species Pseudomonas syringae is divided into numerous pathovars based on host specificity. For example, P. syringae pv. tomato DC3000 is pathogenic on tomato and Arabidopsis, whereas P. syringae pv. syringae 61 is pathogenic on bean. The ability of P. syringae strains to elicit the hypersensitive response (HR) in non-hosts or be pathogenic (or parasitic) in hosts is dependent on the Hrp (type III secretion) system and effector proteins this system is thought to inject into plant cells. To test the role of the Hrp system in determining host range, the hrp/hrc gene cluster (hrpK through hrpR) was deleted from DC3000 and complemented in trans with the orthologous cluster from strain 61. Mutant CUCPB5114 expressing the bean pathogen Hrp system on plasmid pCPP2071 retained the ability of wild-type DC3000 to elicit the HR in bean, to grow and cause bacterial speck in tomato, and to elicit a cultivar-specific (gene-for-gene) HR in tomato plants carrying the Pto resistance gene. However, the symptoms produced in compatible tomato plants involved markedly reduced chlorosis, and CUCPB5114(pCPP2071) did not grow or produce symptoms in Arabidopsis Col-0 although it was weakly virulent in NahG Arabidopsis. A hypersensitive-like collapse was produced by CUCPB5114(pCPP2071) in Arabidopsis Col-0 at 1 x 10(7) CFU/ml, but only if the bacteria also expressed AvrB, which is recognized by the RPM1 resistance gene in Col-0 and confers incompatibility. These observations support the concept that the P. syringae effector proteins, rather than secretion system components, are the primary determinants of host range at both the species and cultivar levels of host specificity.

Arabidopsis↗

PubMed2006

The Salmonella effector protein PipB2 is a linker for kinesin-1.

Understanding the mechanisms of Salmonella virulence is an important challenge. The capacity of this intracellular bacterial pathogen to cause diseases depends on the expression of virulence factors including the second type III secretion system (TTSS-2), which is used to translocate into the eukaryotic cytosol a set of effector proteins that divert the biology of the host cell and shape the bacterial replicative niche. Yet little is known about the eukaryotic functions affected by individual Salmonella effectors. Here we report that the TTSS-2 effector PipB2 interacts with the kinesin light chain, a subunit of the kinesin-1 motor complex that drives anterograde transport along microtubules. Translocation of PipB2 is both necessary and sufficient for the recruitment of kinesin-1 to the membrane of the Salmonella-containing vacuole. In vivo, PipB2 contributes to the attenuation of Salmonella mutant strains in mice. Taken together, our data indicate that the TTSS-2-mediated fine-tuning of kinesin-1 activity associated with the bacterial vacuole is crucial for the virulence of Salmonella.

Animals↗

PubMed2006

Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NFkappaB signaling.

The innate immune response protects numerous organisms, including humans, from the universe of pathogenic molecules, viruses and micro-organisms. Despite its role in promoting pathogen resistance, inappropriate activation and expression of NFkappaB and other immunity-related effector molecules can lead to cancer, inflammation, and other diseases of aging. Understanding the mechanisms leading to immune system activation as well as the short- and long-term consequences of such activation on health and lifespan is therefore critical for the development of beneficial immuno-modulating and longevity-promoting interventions. Mechanisms of innate immunity are highly conserved across species, and we take advantage of genetic tools in the model organism, Drosophila melanogaster, to study the effects of acute and chronic activation of immunity pathways on pathogen resistance and general fitness of adult flies. Our findings indicate that fat body specific overexpression of a putative pathogen recognition molecule, peptidoglycan recognition protein (PGRP-LE), is sufficient for constitutive up-regulation of the immune response and for enhanced pathogen resistance. Primary components of fitness are unaffected by acute activation, but chronic activation leads to an inflammatory state and reduced lifespan. These phenotypes are dependent on the NFkappaB-related transcriptional factor, Relish, and they establish a mechanistic basis for a link between immunity, inflammation, and longevity.

Animals↗

PubMedDate not supplied

Periodontal microflora of HIV infected patients with periodontitis.

The aim of this study was to determine the microbial profile of periodontal lesions in HIV seropositive patients and to compare it with rapidly progressing periodontal lesions in systemically healthy patients. The subgingival microflora of 20 CDC II, 20 CDC III, 20 CDC IV/V and 20 systemically healthy patients with rapidly progressing periodontitis was examined. Four sites with greatest probing depth in each patient were selected for microbiological sampling. The samples were cultured aerobically and anaerobically for bacterial isolation using selective and non-selective media. Isolates were characterized to species level by conventional biochemical tests and various identification kits. The microflora of periodontitis lesions within the three stages of the HIV infection was similar to that of progressing periodontitis in systemically healthy adults including Campylobacter rectus, Capnocytophaga spp., Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Selenomonas spp. and Peptostreptococcus micros. However, HIV seropositive periodontitis lesions harboured a range of exogenous pathogens rarely associated with common types of periodontitis including Staphylococcus aureus, Enterobacter cloaca, Pseudomonas aeruginosa, Candida albicans, Enterococcus faecalis, Enterococcus avium, Clostridium difficile, Aspergillus fumigatus, Klebsiella pneumoniae and Mycoplasma incognitum. The lack of immune effector and regulatory cells in HIV infected patients could in fact explain the increase of some opportunistic pathogens and the characteristic and rapidly progressing nature of the periodontal disease in these patients.

Journal Article↗

PubMed2004

Pneumocystis activates human alveolar macrophage NF-kappaB signaling through mannose receptors.

Alveolar macrophages (AM) represent important effector cells in the innate immune response to the AIDS-related pathogen Pneumocystis, but the early AM host defense signaling events are poorly defined. Using AM from healthy individuals, we showed in the present study that Pneumocystis organisms stimulate AM NF-kappaB p50 and p65 nuclear translocation in a time-dependent and multiplicity-of-infection-dependent manner as determined by electrophoretic mobility shift assay and immunofluorescence microscopy and that NF-kappaB nuclear translocation is associated with I-kappaB phosphorylation. Importantly, competitive inhibition of mannose receptor and targeted short interfering RNA-mediated gene suppression of mannose receptor mRNA and protein is associated with complete elimination of NF-kappaB nuclear translocation in response to Pneumocystis. Furthermore, human immunodeficiency virus (HIV) infection of AM (as a model human disease state of reduced AM mannose receptor expression and function) inhibits Pneumocystis-mediated NF-kappaB nuclear translocation and is associated with reduced I-kappaB phosphorylation and reduced interleukin-8 (IL-8) release. In contrast, NF-kappaB nuclear translocation and IL-8 release in response to lipopolysaccharide are intact in AM from both healthy and HIV-infected individuals, indicating that the observed impairment is not a global disturbance of the NF-kappaB pathway. Thus, in addition to phagocytic and endocytic effector functions, the present study identifies mannose receptors as pattern recognition receptors capable of NF-kappaB activation in response to infectious non-self challenge. AM mannose receptor-mediated NF-kappaB activation may represent an important mechanism of the host cell response to Pneumocystis, and altered NF-kappaB activation in the context of HIV infection may impair a critical innate immune signaling response and may contribute to pathogenesis of opportunistic lung infections.

Adult↗

PubMed2003

The effectiveness and limitations of immune memory: understanding protective immune responses.

Immune memory is the foundation of the practise of vaccination. Research on the molecular and cellular events leading to generation and development of memory T and B lymphocytes explain why there are heightened secondary immune responses after an initial encounter with antigen. In this review, we discuss how clonal expansion, targeted tissue localisation, more efficient antigen recognition and more proficient effector functions contribute to the improved effectiveness of memory cells. Despite the enhanced efficacy of memory cells and the recall immune response, there are numerous experimental and empirical examples in which protection provided by vaccines are short-lived, particularly against pathogens that replicate and cause pathology at their site of entry. In the absence of active immune effector activities, the ability of memory cells to respond quickly enough to control this type of infection is limited. The protective efficacy of bovine herpes virus-1 vaccines in experimental and field challenge conditions are used to illustrate the concept that full protection from disease conferred by vaccination requires the presence of active immune effector mechanisms. Thus, regardless of the many successful technological advances in vaccine design and better understanding of mechanisms underlining induction of memory responses by vaccination, we should recognise that vaccine immunoprophylaxis has limitations. Expectations for vaccines should be realistic and linked to the understanding of host immune responses and knowledge regarding the pathogen and disease pathogenesis.

Animals↗