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Results for “host manipulation”

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PubMed1994

Interactions of bacteria with non-phagocytic cells.

It is becoming increasingly clear that bacterial pathogens can manipulate the host cell to their advantage. Recently, we have learnt more about the different strategies that microorganisms have evolved to subvert normal host-cellular functions. These strategies allow bacteria to gain access to, survive, and replicate within host cells, as well as to spread to neighboring cells, without the need for an extracellular phase. During the next few years, we expect to learn much more about these mechanisms and, in the process, it is likely that we will learn more about the host itself.

Animals↗

PubMed2005

Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 alter mitochondrial morphology during lytic replication.

Epstein-Barr virus (EBV) is a human DNA virus that is responsible for the syndrome infectious mononucleosis, and is associated with several forms of cancer. During both lytic and latent viral infection, viral proteins manipulate the host's cellular components to aid in viral replication and maintenance. Here, it is demonstrated that induction of EBV lytic replication results in a dramatic reorganization of mitochondria accompanied by a significant alteration of mitochondrial membrane potential and a rapid and transient increase in the microtubular cytoskeleton. Moreover, we show that expression of the EBV immediate-early genes BZLF1 and BRLF1 contributes to the mitochondrial alteration but not the increase in the microtubule cytoskeleton, suggesting that the mechanism for the observed cytoplasmic restructuring involves a number of coordinated viral and host proteins.

Cell Line↗

PubMed2005

Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1.

Protozoan parasites of the genus leishmania are obligate intracellular parasites of monocytes and macrophages. These pathogens have evolved to invade the mammalian immune system and typically survive for long periods of time. Leishmania have developed a variety of remarkable strategies to prevent their elimination by both innate and acquired immune effector mechanisms. One particular strategy of interest involves manipulation of host cell regulatory pathways so as to prevent macrophage activation required for efficient microbicidal activity. These interference mechanisms are the main focus of this review. Several lines of evidence have been developed to show that the Src homology-2 domain containing tyrosine phosphatase-1 (SHP-1) becomes activated in leishmania-infected cells and that this contributes to disease pathogenesis. Recent studies aimed at understanding the mechanism responsible for the change in activation state of SHP-1 led to the identification of leishmania EF-1alpha as an SHP-1 binding protein and SHP-1 activator. This was a surprising finding given that this ubiquitous and highly conserved protein plays an essential role in protein translation in both prokaryotic and eukaryotic cells. The role of leishmania EF-1alpha as an SHP-1 activator and its contribution to pathogenesis are reviewed with particular attention to the properties that distinguish it from host EF-1alpha.

Animals↗

PubMed2003

Process design for microbial plastic factories: metabolic engineering of polyhydroxyalkanoates.

Implementing several metabolic engineering strategies, either individually or in combination, it is possible to construct microbial plastic factories to produce a variety of polyhydroxyalkanoate (PHA) biopolymers with desirable structures and material properties. Approaches include external substrate manipulation, inhibitor addition, recombinant gene expression, host cell genome manipulation and, most recently, protein engineering of PHA biosynthetic enzymes. In addition, mathematical models and molecular methods can be used to elucidate metabolically engineered systems and to identify targets for performance improvement.

Acyltransferases↗

PubMed2005

Post-translational control of chemokines: a role for decoy receptors?

It is well-established that chemokines play a critical role in the orchestration of inflammation and immunity. Interactions between chemokines and their receptors are essential for the homing of specific subsets of leukocytes to their functional microenvironments. They also influence other diverse biological processes such as development, leukocyte activation, Th1/Th2 polarisation, tumour metastasis, angiogenesis, and HIV pathogenesis. However, despite their importance, only now are we beginning to understand the complex regulation brought to bear on these molecules. In this review, we discuss a number of these key chemokine regulators that exert their influence once these proteins have been synthesised. We examine (i) chemokine storage, release, and presentation, (ii) protease regulation, (iii) viral manipulation of host chemokines, and (iv) natural mammalian receptor antagonists. Principally, the growing evidence for a role for decoy receptors in the chemokine system is discussed. In particular, the potential decoy function of the 'silent' pro-inflammatory chemokine receptor D6 is described alongside two other candidate decoy receptor molecules, DARC, and CCX-CKR. Dissecting the biological and pathological function of these chemokine controllers will lead to a deeper understanding of chemokine regulation, and may reveal novel strategies to therapeutically modify the chemokine system.

Animals↗

PubMed2006

Interaction between stromal fibroblasts and colorectal cancer cells in the expression of vascular endothelial growth factor.

BACKGROUND: Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been implicated in metastasis of colorectal cancer (CRC). The present study aimed to clarify whether cancer-stromal interaction induces the production of VEGF. MATERIALS AND METHODS: Human colonic fibroblasts (CCD-18Co) and CRC (SW480, SW620) cells were analyzed in this study. The cell cycle of colonic fibroblasts during co-culture was analyzed by flow cytometry. VEGF and TGF-beta1 released into the conditioned media in co-culture models were measured. Northern blot with human specific VEGF probe was performed to identify the expression of VEGF in this model. RESULTS: Co-culture of colonic fibroblasts with CRC cells increased the viability of fibroblasts during co-culture. Cell cycle analysis revealed that most of the fibroblasts co-cultured with CRC cells were arrested at G1 phase and few cells were in sub-G1 phase that indicates apoptosis. Although VEGF protein was detected in the culture media of all of the monocultures, co-cultivation of CRC with fibroblasts resulted in synergistic increase of VEGF production compared with monocultures. However TGF-beta1 protein was not detected in any conditioned medium. VEGF mRNA was detected in both CRC and fibroblasts. Under co-culture condition, an abundance of VEGF mRNA expression was noted in fibroblasts relative to CRC cells. CONCLUSIONS: The present study suggests that CRC manipulates the host stroma to suppress apoptosis and up-regulate VEGF production.

Apoptosis↗

PubMed2004

Pleiotropic function of Toll-like receptors.

A group of type I transmembrane proteins, Toll-like receptors (TLRs) discriminate various microorganism-associated molecular structures that can function as immune adjuvants. Each TLR signaling has an overlapping but distinct function, which largely depends on intracellular adaptor molecules. Clarifying the functions and signaling of TLRs should provide us with critical information for manipulating the host defense mechanism.

Animals↗

PubMed2005

Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle.

Microbial pathogens have developed a variety of strategies to manipulate host-cell functions, presumably for their own benefit. We propose the term "cyclomodulins" to describe the growing family of bacterial toxins and effectors that interfere with the eukaryotic cell cycle. Inhibitory cyclomodulins, such as cytolethal distending toxins (CDTs) and the cycle inhibiting factor (Cif), block mitosis and might constitute powerful weapons for immune evasion by inhibiting clonal expansion of lymphocytes. Cell-cycle inhibitors might also impair epithelial-barrier integrity, allowing the entry of pathogenic bacteria into the body or prolonging their local existence by blocking the shedding of epithelia. Conversely, cyclomodulins that promote cellular proliferation, such as the cytotoxic necrotizing factor (CNF), exemplify another subversion mechanism by interfering with pathways of cell differentiation and development. The role of these cyclomodulins in bacterial virulence and carcinogenesis awaits further study and will delineate new perspectives in basic research and therapeutic applications.

Animals↗

PubMed2003

Phosphoinositide signaling disorders in human diseases.

Phosphoinositides (PIs) play an essential role in diverse cellular functions. Their intracellular level is strictly regulated by specific PI kinases, phosphatases and phospholipases. Recent discoveries indicate that dysfunctions in the control of their level often lead to pathologies. This review will focus on some human diseases whose etiologies involve PI-metabolizing enzymes. The role of PTEN (phosphatase and tensin homolog deleted on chromosome ten) in cancer, the impact of the Src homology 2-containing inositol-5-phosphatase phosphatases in acute myeloid leukemia or diabetes, the involvement of myotubularin family members in genetic diseases and the implication of OCRL1 in Lowe syndrome will be emphasized. We will also review how some bacterial pathogens have evolved strategies to specifically manipulate the host cell PI metabolism to efficiently infect them.

1-Phosphatidylinositol 4-Kinase↗

PubMed2003

Microbial globins.

Globins are an ancient and diverse superfamily of proteins. The globins of microorganisms were relatively ignored for many decades after their discovery by Warburg in the 1930s and rediscovery by Keilin in the 1950s. The relatively recent focus on them has been fuelled by recognition of their structural diversity and fine-tuning to fulfill (probably) discrete functions but particularly by the finding that a major role of certain globins is in protection from the stresses caused by exposure to nitric oxide (NO)--itself a molecule that has attracted intense curiosity recently. At least three classes of microbial globin are recognised, all having features of the classical globin protein fold. The first class is typified by the myoglobin-like haemprotein Vgb from the bacterium Vitreoscilla, which has attracted considerable attention because of its ability to improve growth and metabolism for biotechnological gain in a variety of host cells, even though its physiological function is not fully understood. The truncated globins are widely distributed in bacteria, microbial eukaryotes as well as plants and are characterised by being 20-40 residues shorter than Vgb. The polypeptide is folded into a two-over-two helical structure while retaining the essential features of the globin superfamily. Roles in oxygen and NO metabolism have been proposed. The third and best understood class comprises the flavohaemoglobins, which were first discovered and partly characterised in yeast. These are distinguished by the presence of an additional domain with binding sites for FAD and NAD(P)H. Widely distributed in bacteria, these proteins undoubtedly confer protection from NO and nitrosative stresses, probably by direct consumption of NO. However, a bewildering array of enzymatic capabilities and the presence of an active site in the haem pocket reminiscent of peroxidases hint at other functions. A full understanding of microbial globins promises advances in controlling the interactions of pathogenic bacteria with their animal and plant hosts, and manipulations of microbial oxygen transfer with biotechnological applications.

Amino Acid Sequence↗

PubMed2000

The role of quorum sensing in the in vivo virulence of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide variety of infections. The cell-density-dependent signaling mechanisms known as quorum sensing play a role in several of these infections including corneal, lung and burn wound infections. In addition, the quorum-sensing systems contribute to the ability of P. aeruginosa to form biofilms on medically important devices. The quorum-sensing systems accomplish their effect by controlling the production of different virulence factors and by manipulating the host immune response.

Animals↗

PubMed2001

Controlling transgene integration in plants.

The creation of transgenic plants has brought significant advances to light in plant biotechnology. However, in spite of the fact that transgenic plants are beginning to be grown widely, controlled transgene integration into a pre-determined site remains to be achieved. Here we suggest two alternative approaches for gene targeting in plants: manipulating the host and donor sequence, and targeting during active homologous recombination stages.

Arabidopsis↗

PubMed1993

Malarial parasites and antioxidant nutrients.

Susceptibility to oxidative stress is a well-established feature of the malarial parasite. Pharmacologists have taken advantage of this property to design highly effective pro-oxidant antimalarial drugs. Less well appreciated is the fact that nutritional manipulation of host oxidative stress status by dietary means can have a profound effect on the growth of the parasite. In particular, rapid induction of vitamin E deficiency in mice by feeding highly unsaturated fatty acids (fish oil) strongly suppresses plasmodial growth. Likewise, the status of other antioxidant nutrients (e.g., riboflavin or vitamin C) may also influence the course of malarial infection under certain conditions. A combined nutritional pharmacology approach may offer some promise in controlling malaria.

Animals↗

PubMed2001

Group A Streptococcus tissue invasion by CD44-mediated cell signalling.

Streptococcus pyogenes (also known as group A Streptococcus, GAS), the agent of streptococcal sore throat and invasive soft-tissue infections, attaches to human pharyngeal or skin epithelial cells through specific recognition of its hyaluronic acid capsular polysaccharide by the hyaluronic-acid-binding protein CD44 (refs 1, 2). Because ligation of CD44 by hyaluronic acid can induce epithelial cell movement on extracellular matrix, we investigated whether molecular mimicry by the GAS hyaluronic acid capsule might induce similar cellular responses. Here we show that CD44-dependent GAS binding to polarized monolayers of human keratinocytes induced marked cytoskeletal rearrangements manifested by membrane ruffling and disruption of intercellular junctions. Transduction of the signal induced by GAS binding to CD44 on the keratinocyte surface involved Rac1 and the cytoskeleton linker protein ezrin, as well as tyrosine phosphorylation of cellular proteins. Studies of bacterial translocation in two models of human skin indicated that cell signalling triggered by interaction of the GAS capsule with CD44 opened intercellular junctions and promoted tissue penetration by GAS through a paracellular route. These results support a model of host cytoskeleton manipulation and tissue invasion by an extracellular bacterial pathogen.

Bacterial Adhesion↗

PubMed2006

Wolbachia infection influences the development of Culex pipiens embryo in incompatible crosses.

Wolbachia are maternally inherited endosymbiotic bacteria that infect many arthropod species and have evolved several different ways for manipulating their host, the most frequent being cytoplasmic incompatibility (CI). CI leads to embryo death in crosses between infected males and uninfected females, as well as in crosses between individuals infected by incompatible Wolbachia strains. In the mosquito Culex pipiens, previous studies suggested developmental variation in embryos stemming from different incompatible crosses. We have investigated this variation in different incompatible crosses. Unhatched eggs were separated into three classes based upon the developmental stage reached by the embryos. We found that incompatible crosses involving uninfected females produced only embryos whose development was arrested at a very early stage, irrespective of the Wolbachia variant infecting the male. These results differ from other host species where a developmental gradient that could reach late stages of embryogenesis or even living larvae was observed, and indicate a novel peculiarity of CI mechanism in C. pipiens. By contrast, all incompatible crosses with infected C. pipiens females produced embryos of all three classes. The proportion of embryo classes appeared to be associated with the strains involved, suggesting specific CI properties in different incompatible crosses. In addition, the contribution of parental genome was characterized in embryo classes using molecular markers for each chromosome. Embryo phenotypes appeared linked to the paternal chromosomes' contribution, as described in Drosophila simulans. However, this contribution varied according to maternal infection and independently of male factors.

Animals↗

PubMed2004

Activation of caspase-3 by the Dot/Icm virulence system is essential for arrested biogenesis of the Legionella-containing phagosome.

The Dot/Icm type IV secretion system of Legionella pneumophila is essential for evasion of endocytic fusion and for activation of caspase-3 during early stages of infection of macrophages, but the mechanisms of manipulating these host cell processes are not known. Here, we show that caspase-3 activation by L. pneumophila is independent of all the known apoptotic pathways that converge on the activation of caspase-3. The cytoplasmic proteins IcmS, IcmR and IcmQ, which are involved in secretion of Dot/Icm effectors, are required for caspase-3 activation. Pretreatment of U937 macrophages and human peripheral blood monocytes (hPBM) with the capase-3 inhibitor (DEVD-fmk) or the paninhibitor of caspases (Z-VAD-fmk) before infection blocks intracellular replication of L. pneumophila in a dose-dependent manner. Inhibition of caspase-3 results in co-localization of the L. pneumophila-containing phagosome (LCP) with the late endosomal/lysosomal marker Lamp-2, and the LCP contains lysosomal enzymes, similar to the dotA mutant, which is defective in caspase-3 activation. However, activation of caspase-3 before infection does not rescue the replication defect of the dotA mutant. Interestingly, inhibition of caspase-3 after a 15 or 30 min infection period by the parental strain has no detectable effect on the formation of a replicative niche. The Dot/Icm-mediated activation of caspase-3 by L. pneumophila specifically cleaves, in a dose- and time-dependent manner, the Rab5 effector Rabaptin-5, which maintains Rab5-GTP on the endosomal membrane. In addition, PI3 kinase, which is a crucial effector of Rab5 downstream of Rababptin-5, is not required for intracellular replication. Using single-cell analysis, we show that apoptosis is not evident in the infected cell until bacterial replication results in > 20 bacteria per cell. We conclude that activation of caspase-3 by the Dot/Icm virulence system of L. pneumophila is essential for halting biogenesis of the LCP through the endosomal/lysosomal pathway, and that this is associated with the cleavage of Rabpatin-5.

Antigens, CD↗

PubMed1998

HIV-1 Tat elongates the G1 phase and indirectly promotes HIV-1 gene expression in cells of glial origin.

Human immunodeficiency virus type-1 (HIV-1) infection of the central nervous system (CNS) gives rise to many of the neurological complications in patients with AIDS. Infection of microglial cells and astrocytes in the brain promotes the release of HIV-1 Tat and other candidate neurotoxins that may be associated with the widespread neuropathology. To examine the contribution of HIV-1 Tat to the interplay between virus and CNS cells, the human astrocytic cell line, U-87MG, was treated with recombinant Tat protein. Fluorescence-activated cell sorting analysis indicated that Tat induces a G1 arrest in these cells. Consistent with this observation, lower levels of cyclin E-Cdk2 kinase activity and phosphorylated Rb were detected in the Tat-treated cells compared with the control cells. Interestingly, our observations indicate that the underphosphorylated form of Rb that is prevalent in Tat-treated cells promotes HIV-1 transcription by a mechanism involving the NF-kappaB enhancer region. Taken together, the data presented here provide the first evidence that the HIV-1 regulatory protein, Tat, may manipulate the host cell cycle to promote viral gene expression. The significance of these findings relates to the current hypothesis that indirect effects of HIV-1 infection of the CNS may contribute to the neurological complications associated with AIDS dementia complex.

Astrocytes↗

PubMed2005

WAVE2 signaling mediates invasion of polarized epithelial cells by Salmonella typhimurium.

The bacterial pathogen Salmonella penetrates the intestinal epithelium by inducing its own phagocytosis into epithelial cells. The dramatic reorganization of the actin cytoskeleton required for internalization is driven by bacterial manipulation of host signaling pathways, including activation of the Rho family GTPase Rac1 and subsequent activation of the Arp2/3 complex. However, the mechanisms linking these two events remain poorly understood. Rac1 is thought to promote activation of the Arp2/3 complex through its interaction with suppressor of cAMP receptor/WASP family verprolin-homologous (SCAR/WAVE) family proteins, but this interaction is apparently indirect. Two different Rac1 effectors have been shown to bind WAVE2: IRSp53, the SH3 domain of which binds the WAVE2 proline-rich domain, and PIR121/Sra-1, which forms a pentameric complex containing WAVE, Abi1, Nap1, and HSPC300. However, the extent to which each of these complexes contributes to Arp2/3 complex activation in the context of Salmonella infection is unclear. Here, we show that WAVE2 is necessary for efficient invasion of epithelial cells by Salmonella typhimurium. We found that although Salmonella infection strongly promotes the formation of an IRSp53/WAVE2 complex, IRSp53 is not necessary for bacterial internalization. In contrast, disruption of the PIR121/Nap1/Abi1/WAVE2/HSPC300 complex potently inhibits bacterial uptake. These results indicate that WAVE2 is an important component in signaling pathways leading to Salmonella invasion. Although infection leads to the formation of an IRSp53/WAVE2 complex, it is the association of WAVE2 with the Abi1/Nap1/PIR121/HSPC300 complex that regulates bacterial internalization.

Adaptor Proteins, Signal Transducing↗