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PubMedDate not supplied

Genetic mosaicism and the control of cancer.

The susceptibility of animal cells to certain lethal agents, including a variety of cytotoxic drugs, is genetically determined; cells which are otherwise identical may therefore differ in terms of which agents are lethal for them. If such genetic diversity existed within a tissue, exposure to any of these lethal agents would not destroy every cell, but only that fraction of the population that was susceptible. In contrast, if a clone of malignant cells arose from any single cell within such a tissue, the entire malignant clone should be susceptible to destruction by whatever agent its progenitor cells was susceptible to. Treatment of a tumor in a host whose tissues displayed such genetic mosaicism might therefore possess the potential for destroying all tumor cells, at the cost of destroying only a fraction of the normal cells. Prophylactic induction of such mosaicism in normal hosts by genetic manipulation represents a potential future strategy for cancer control. Evidence is presented suggesting that women heterozygous for deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-transferase may constitute naturally occurring examples of such exploitable mosaicism.

Genetic Engineering↗

PubMed2006

Salmonella type III secretion effectors: pulling the host cell's strings.

The enteric pathogen Salmonella employs type III secretion systems to transport a cocktail of effector proteins directly into its host cell. These effectors act in concert to control a variety of host cell processes to successfully invade intestinal cells and to establish an intracellular, replication-permissive niche. Recent studies reveal new insights into the molecular mechanisms that underlie effector protein injection, host cell invasion, and manipulation of vesicle trafficking induced by the interplay between multiple effectors and host systems. These findings corroborate the importance of spatio-temporal regulation of effector protein function for fine-tuned modulation of the host cell machinery.

Animals↗

PubMed2005

Rotting softly and stealthily.

The soft rot erwiniae, which are plant pathogens on potato and other crops world-wide, synthesize and secrete large quantities of plant cell wall degrading enzymes that are responsible for the soft rot phenotype, earning them the epithet 'brute force' pathogens. They have been distinguished from classic 'stealth' pathogens, such as Pseudomonas syringae, which possesses an extensive battery of Type III secreted effector proteins and phytotoxins to manipulate and suppress host defences. However, recent studies, including whole-genome sequencing, are revealing many components of stealth pathogenesis within the soft rot erwiniae (SRE), suggesting that 'stealth' and 'brute force' should not be regarded as mutually exclusive modes of pathogenesis.

Cell Wall↗

PubMed1996

The pathogenesis of Staphylococcus aureus in the trauma patient and potential future therapies.

BACKGROUND: Staphylococcus aureus is the most frequently isolated pathogen in the trauma patient and uses multiple virulent factors to cause infection. At the cellular level, infection begins with the prokaryotic bacterial cell manipulating the eukaryotic host cell through its virulent factors. Researching this cellular interaction by describing the mechanisms of actions of various virulent factors may lead to new preventive therapies which will make the trauma patient less susceptible to S aureus infections. METHODS: Surgical, medical, and microbial literature was reviewed to provide an update on S aureus pathogenesis. RESULTS: Novel future therapies, in addition to antibiotics, are being devised based on understanding the molecular nature of S aureus pathogenesis. CONCLUSION: The impact of S aureus on trauma will increase as S aureus develops more antibiotic resistance and as the trauma population becomes older and includes an increasing proportion of immunocompromised patients. To meet the challenge of increased virulence, trauma surgeons should be directly involved in the research of microbial pathogenesis.

Bacterial Adhesion↗

PubMed1997

Immunological interactions between Trichinella spiralis and Heligmosomoides polygyrus: cross reactivity between muscle larvae and antibodies raised to unrelated antigens.

It is documented that concurrent infections in mice with the 2 unrelated nematode parasites, Heligmosomoides polygyrus and Trichinella spiralis, can result in delayed rejection of the latter species. The basis of this immunological interference is not completely understood, but a possibility exists that antibodies induced by 1 species may interact with antigens produced by the other parasite. Therefore, it was investigated whether H. polygyrus infections may induce the production of antibodies which could cross react with T. spiralis muscle larval (m.l.) antigens. The results shown here indicate that this assumption is correct, and there is cross reactivity between antibodies produced against H. polygyrus, and T. spiralis m.l. antigens. Furthermore, antibodies which were not specific for either species were also able to bind to T. spiralis m.l. This is in agreement with recent evidence which has shown that antibodies that are not specific for H. polygyrus may still be absorbed by an H. polygyrus homogenate. It is considered that the binding of these antibodies may be involved in manipulation of the host immune response by T. spiralis.

Animals↗

PubMed1988

Multiple system organ failure.

Multiple system organ failure represents the final common pathway to a fatal outcome in severely infected patients. Despite the development of extensive support technology, the mortality rate in this group of patients remains high: in excess of 50 per cent. This rate underscores the need for newer treatment modalities. Numerous mediators/effectors appear to play a role in the complex evolution of the process. The independent and interactive effects of these numerous mediators/effectors remain to be elucidated. Future therapies will need to address immunomodulation of the host and biochemical manipulation of the fundamental process before significant improvement in outcome can be expected.

Critical Care↗

PubMed2002

Crohn's disease.

Crohn's disease is a disorder mediated by T lymphocytes which arises in genetically susceptible individuals as a result of a breakdown in the regulatory constraints on mucosal immune responses to enteric bacteria. Regulation of immune reactivity to enteric antigens has improved understanding of the pathophysiological mechanisms of Crohn's disease, and has expanded therapeutic options for patients with this disorder. Disease heterogeneity is probable, with various underlying defects associated with a similar pathophysiological outcome. Although most conventional drug treatments are directed at modification of host response, therapeutic manipulation of the enteric flora is becoming a realistic option.

Animals↗

PubMed2002

Eukaryotic genes in Mycobacterium tuberculosis could have a role in pathogenesis and immunomodulation.

Acquisition of new genetic material through horizontal gene transfer has been an important feature in the evolution of many pathogenic bacteria. Here, we report the presence of 19 genes of eukaryotic origin in the genome of Mycobacterium tuberculosis, some of which are unique to the M. tuberculosis complex. These genes, having been retained in the genome through selective advantage, most probably have key functions in the organism and in mammalian tuberculosis. We explore the role these genes might have in manipulation of the host immune system by altering the balance of steroid hormones.

Amino Acid Sequence↗

PubMed1997

Immunological control of gastrointestinal nematode infections.

Control of nematode parasitism by an active manipulation of the host immune response has been a goal of veterinary and medical parasitologists for decades. The reality of achieving this goal has been questioned vigorously and demonstrations of the feasibility of using immunological control under field conditions are minimal. Nevertheless, with the rapid growth of modern biotechnology and the identification of novel parasite molecules as vaccine targets, the potential for success in this area has recently generated considerable excitement. The induction and regulation of the ruminant immune response against nematode parasites can be controlled either by management programs which include anthelmintic treatment or by vaccination. Both approaches will be discussed in this session.

Animals↗

PubMed2000

Infectious parthenogenesis.

Parthenogenesis-inducing Wolbachia bacteria are reproductive parasites that cause infected female wasps to produce daughters without mating. This manipulation of the host's reproduction enhances the transmission of Wolbachia to future generations because the bacteria are passed on vertically only from mothers to daughters. Males are dead ends for cytoplasmically inherited bacteria: they do not pass them on to their offspring. Vertical transmission of Wolbachia has been previously considered to be the main mode of transmission. Here we report frequent horizontal transmission from infected to uninfected wasp larvae sharing a common food source. The transferred Wolbachia are then vertically transmitted to the new host's offspring. This natural and unexpectedly frequent horizontal transfer of parthenogensis-inducing Wolbachia intraspecifically has important implications for the co-evolution of Wolbachia and their host.

Animals↗

PubMed1980

Human breast-cancer xenografts in immune-suppressed mice.

Eight serially transplantable human breast-cancer xenograft lines have been established in immune-suppressed mice. Specimens from 102 primary and secondary lesions obtained at surgery from 80 patients were implanted into mice immune-suppressed by thymectomy and whole-body irradiation. A number of variations of implantation site, transplantation technique, method of immune suppression and hormonal manipulation of the host were tried in an attempt to increase the take rate, but without success. The 8 lines established have been serially transplanted into further immune-suppressed mice for at least 2 passages, and appear to maintain characteristic human histopathology, chromosome number and tumour-marker production. None of the tumours show hormone sensitivity. The poor take rate may be a reflection of the biological nature of breast cancer rather than a failure of the immune-deprivation technique, as many other human tumours grow well as xenografts in this system.

Animals↗

PubMed2003

Directed expression of the HIV-1 accessory protein Vpu in Drosophila fat-body cells inhibits Toll-dependent immune responses.

Human immunodeficiency virus 1 (HIV-1) expresses several accessory proteins that manipulate various host-cell processes to achieve optimum replicative efficiency. One of them, viral protein U (Vpu), has been shown to interfere with the cellular degradation machinery through interaction with SCF(beta-TrCP) complexes. To learn more about Vpu function in vivo, we used the genetically tractable fruit fly, Drosophila melanogaster. Our results show that the directed expression of Vpu, but not the non-phosphorylated form, Vpu2/6, in fat-body cells affects Drosophila antimicrobial responses. In flies, the Toll and Imd pathways regulate antimicrobial-peptide gene expression. We show that Vpu specifically affects Toll pathway activation by inhibiting Cactus degradation. Given the conservation of the Toll/nuclear factor-kappa B (NF-kappa B) signalling pathways between flies and mammals, our results suggest a function for Vpu in the inhibition of host NF-kappa B-mediated innate immune defences and provide a powerful genetic approach for studying Vpu inhibition of NF-kappa B signalling in vivo.

Animals↗

PubMed2002

Heterogeneity in the effect of different ixodid tick species on human natural killer cell activity.

Tick saliva plays a vital role in blood-feeding, including manipulation of the host response to tick infestation. Furthermore, a diverse number of tick-borne pathogens are transmitted to vertebrate hosts via tick saliva, some of which exploit the immunomodulatory activities of their vector's saliva. We report that salivary gland extracts (SGE) derived from Dermacentor reticulatus adult ticks induce a decrease in the natural killer (NK) activity of effector cells obtained from healthy human blood donors. The decrease was observed with SGE from both female and male D. reticulatus fed for either 3 or 5 days on mice, but no significant effect was observed with SGE from unfed ticks or ticks that had fed for 1 day. These results indicate that the tick anti-NK factor(s) is only active after blood-feeding has commenced. Microscopic examination revealed that the first step of NK activity, namely effector/target cell conjugate formation, was affected by SGE. The observed reduction in conjugate formation occurred when effector (but not target) cells were treated with SGE for 30 min, and the effect persisted after 12 h of treatment. Similar but less potent anti-NK activity was detected for SGE from Amblyomma variegatum and Haemaphysalis inermis. By contrast, SGE derived from Ixodes ricinus and Rhipicephalus appendiculatus female ticks did not decrease NK activity. The apparent absence of such activity in these two important vectors of tick-borne viruses suggests that control of NK cells does not play an important role in promoting virus transmission, at least for these particular species.

Animals↗

PubMed2000

IpgD, a protein secreted by the type III secretion machinery of Shigella flexneri, is chaperoned by IpgE and implicated in entry focus formation.

Invasion of epithelial cells by Shigella flexneri involves entry and intercellular dissemination. Entry of bacteria into non-phagocytic cells requires the IpaA-D proteins that are secreted by the Mxi-Spa type III secretion machinery. Type III secretion systems are found in several Gram-negative pathogens and serve to inject bacterial effector proteins directly into the cytoplasm of host cells. In this study, we have analysed the IpgD protein of S. flexneri, the gene of which is located on the virulence plasmid at the 5' end of the mxi-spa locus. We have shown that IpgD (i) is stored in the bacterial cytoplasm in association with a specific chaperone, IpgE; (ii) is secreted by the Mxi-Spa type III secretion system in amounts similar to those of the IpaA-D proteins; (iii) is associated with IpaA in the extracellular medium; and (iv) is involved in the modulation of the host cell response after contact of the bacterium with epithelial cells. This suggests that IpgD is an effector that might be injected into host cells to manipulate cellular processes during infection.

Bacterial Proteins↗

PubMed2001

Childhood tuberculosis: treatment strategies and recent advances.

Over the past 20 years, several major studies have shown that 6-month therapy, initially using isoniazid, rifampin and pyrazinamide, is highly effective and extremely safe for the treatment of most forms of childhood tuberculosis. The various drug schedules and frequency of administration will be reviewed. Directly observed therapy is an essential component of a paediatric tuberculosis treatment plan, though using it does not solve all problems with adherence to treatment. As the rates of drug-resistant tuberculosis increase around the world, special aspects of paediatric tuberculosis will have to be considered when designing treatment regimens for children. Finally, the next frontier of antituberculosis therapy may be the manipulation of the host immune system.

AIDS-Related Opportunistic Infections↗

PubMed1994

Cytokine regulation of mucosal responses: a rational basis for new vaccine delivery strategies.

In this review, cytokine regulation of mucosal responses is discussed in relation to the mucosal immune network and regulation of IgA responses. Based on this understanding, aspects of gene therapy for manipulation of the host environment and vaccine delivery systems are discussed. Although evidence obtained in vitro is briefly reviewed the general focus of this article is on evidence obtained from models in vivo.

Animals↗

PubMed2003

Amino acids of the bacterial toxin SopE involved in G nucleotide exchange on Cdc42.

RhoGTPases are central switches in all eukaryotic cells. There are at least two known families of guanine nucleotide exchange factors that can activate RhoGTPases: the Dbl-like eukaryotic G nucleotide exchange factors and the SopE-like toxins of pathogenic bacteria, which are injected into host cells to manipulate signaling. Both families have strikingly different sequences, structures, and catalytic core elements. This suggests that they have emerged by convergent evolution. Nevertheless, both families of G nucleotide exchange factors also share some similarities: (a) both rearrange the G nucleotide binding site of RhoGTPases into virtually identical conformations, and (b) two SopE residues (Gln-109SopE and Asp-124SopE) engage Cdc42 in a similar way as equivalent residues of Dbl-like G nucleotide exchange factors (i.e. Asn-810Dbs and Glu-639Dbs). The functional importance of these observations has remained unclear. Here, we have analyzed the effect of amino acid substitutions at selected SopE residues implicated in catalysis (Asp-124SopE, Gln-109SopE, Asp-103SopE, Lys-198SopE, and Gly-168SopE) on in vitro catalysis of G nucleotide release from Cdc42 and on in vivo activity. Substitutions at Asp-124SopE, Gln-109SopE, and Gly-168SopE severely reduced the SopE activity. Slight defects were observed with Asp-103SopE variants, whereas Lys-198SopE was not found to be required in vitro or in vivo. Our results demonstrate that G nucleotide exchange by SopE involves both catalytic elements unique to the SopE family (i.e. 166GAGA169 loop, Asp-103SopE) and amino acid contacts resembling those of key residues of Dbl-like guanine nucleotide exchange factors. Therefore, besides all of the differences, the catalytic mechanisms of the SopE and the Dbl families share some key functional aspects.

Actins↗

PubMed2005

DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN.

During schistosomiasis, parasite-derived glycoconjugates play a key role in manipulation of the host immune response, associated with persistence of the parasite. Among the candidate host receptors that are triggered by glycoconjugates are C-type lectins (CLRs) on dendritic cells (DCs), which in concerted action with Toll-like receptors determine the balance in DCs between induction of immunity versus tolerance. Here we report that the CLR DC-SIGN mediates adhesion of DCs to authentic glycolipids derived from Schistosoma mansoni cercariae and their excretory/secretory products. Structural characterization of the glycolipids, in combination with solid phase and cellular binding studies revealed that DC-SIGN binds to the carbohydrate moieties of both glycosphingolipid species with Galbeta1-4(Fucalpha1-3)GlcNAc (Lewis(X)) and Fucalpha1-3Galbeta1-4(Fucalpha1-3)GlcNAc (pseudo-Lewis(Y)) determinants. Importantly, these data indicate that surveying DCs in the skin may encounter schistosome-derived glycolipids immediately after infection. Recent analysis of crystals of the carbohydrate binding domain of DC-SIGN bound to Lewis(X) provided insight into the ability of DC-SIGN to bind fucosylated ligands. Using molecular modeling we showed that the observed binding of the schistosome-specific pseudo-Lewis(Y) to DC-SIGN is not directly compatible with the model described. To fit pseudo-Lewis(Y) into the model, the orientation of the side chain of Phe(313) in the secondary binding site of DC-SIGN was slightly changed, which results in a perfect stacking of Phe(313) with the hydrophobic side of the galactose-linked fucose of pseudo-Lewis(Y). We propose that pathogens such as S. mansoni may use the observed flexibility in the secondary binding site of DC-SIGN to target DCs, which may contribute to immune escape.

Animals↗