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PubMed2002

Parasitic adaptive mechanisms in infection by leishmania.

Leishmania are a resilient group of intracellular parasites that infect macrophages. The resultant complex of diseases, or leishmaniases, caused by the parasites affect over twelve million people worldwide. Leishmania have developed unique adaptive mechanisms to ensure their survival in the harsh environments faced throughout their life cycle. These parasites must not only contend with the hostile digestive conditions found within the sand fly vector, but they must also avoid destruction by the host immune system while in the bloodstream, before entering the macrophage. To do so, Leishmania express unique lipophosphoglycan (LPG) molecules and the metalloprotease gp63, among other proteins, on their cell surface. To enter the macrophage, Leishmania utilizes a variety of cellular receptors to mediate endocytosis. Once inside the macrophage, Leishmania is protected from phagolysosome degradation by a variety of adaptations to inhibit cellular defense mechanisms. These include the inhibition of phagosome-endosome fusion, hydrolytic enzymes, cell signaling pathways, nitric oxide production, and cytokine production. While other parasites can also infect macrophages, Leishmania is distinctive in that it not only relies on its own defenses to survive and reproduce within the macrophage phagolysosome, but Leishmania also manipulates the host immune response in order to protect itself and to gain entry into the cell. These unique adaptive mechanisms help promote Leishmania survival.

Adaptation, Biological↗
PubMed2005

Genome of deerpox virus.

Deerpox virus (DPV), an uncharacterized and unclassified member of the Poxviridae, has been isolated from North American free-ranging mule deer (Odocoileus hemionus) exhibiting mucocutaneous disease. Here we report the genomic sequence and comparative analysis of two pathogenic DPV isolates, W-848-83 (W83) and W-1170-84 (W84). The W83 and W84 genomes are 166 and 170 kbp, containing 169 and 170 putative genes, respectively. Nucleotide identity between DPVs is 95% over the central 157 kbp. W83 and W84 share similar gene orders and code for similar replicative, structural, virulence, and host range functions. DPV open reading frames (ORFs) with putative virulence and host range functions include those similar to cytokine receptors (R), including gamma interferon receptor (IFN-gammaR), interleukin 1 receptor (IL-1R), and type 8 CC-chemokine receptors; cytokine binding proteins (BP), including IL-18BP, IFN-alpha/betaBP, and tumor necrosis factor binding protein (TNFBP); serpins; and homologues of vaccinia virus (VACV) E3L, K3L, and A52R proteins. DPVs also encode distinct forms of major histocompatibility complex class I, C-type lectin-like protein, and transforming growth factor beta1 (TGF-beta1), a protein not previously described in a mammalian chordopoxvirus. Notably, DPV encodes homologues of cellular endothelin 2 and IL-1R antagonist, novel poxviral genes also likely involved in the manipulation of host responses. W83 and W84 differ from each other by the presence or absence of five ORFs. Specifically, homologues of a CD30 TNFR family protein, swinepox virus SPV019, and VACV E11L core protein are absent in W83, and homologues of TGF-beta1 and lumpy skin disease virus LSDV023 are absent in W84. Phylogenetic analysis indicates that DPVs are genetically distinct from viruses of other characterized poxviral genera and that they likely comprise a new genus within the subfamily Chordopoxvirinae.

Amino Acid Sequence↗
PubMed1999

A role for host phosphoinositide 3-kinase and cytoskeletal remodeling during Cryptosporidium parvum infection.

Cryptosporidium parvum preferentially infects epithelial cells lining the intestinal mucosa of mammalian hosts. Parasite development and propagation occurs within a unique intracellular but extracytoplasmic parasitophorous vacuole at the apical surface of infected cells. Parasite-induced host cell signaling events and subsequent cytoskeletal remodeling were investigated by using cultured bovine fallopian tube epithelial (BFTE) cells inoculated with C. parvum sporozoites. Indirect-immunofluorescence microscopy detected host tyrosine phosphorylation within 30 s of inoculation. At >30 min postinoculation, actin aggregates were detected at the site of parasite attachment by fluorescein isothiocyanate-conjugated phalloidin staining as well as by indirect immunolabeling with monoclonal anti-actin. The actin-binding protein villin was also detected in focal aggregates at the site of attachment. Host cytoskeletal rearrangement persisted for the duration of the parasitophorous vacuole and contributed to the formation of long, branched microvilli clustered around the cryptosporidial vacuole. The phosphoinositide 3-kinase inhibitor wortmannin significantly inhibited (P < 0.05) C. parvum infection when BFTE cells were pretreated for 60 min at 37 degreesC prior to inoculation. Similarly, treatment of BFTE cells with the protein kinase inhibitors genistein and staurosporine and the cytoskeletally acting compounds 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazapine, cytochalasin D, and 2,3-butanedione monoxime significantly inhibited (P < 0.05) in vitro infection at 24 h postinoculation. These findings demonstrate a prominent role for phosphoinositide 3-kinase activity during the early C. parvum infection process and suggest that manipulation of host signaling pathways results in actin rearrangement at the site of sporozoite attachment.

Animals↗
PubMed2000

Differential influence of Pomphorhynchus laevis (Acanthocephala) on the behaviour of native and invader gammarid species.

Although various species of acanthocephalan parasites can increase the vulnerability of their amphipod intermediate hosts to predation, particularly by altering their photophobic behaviour, their influence on the structure of amphipod communities and the success of invader species has so far received little attention. We compared the prevalence and behavioural influence of a fish acanthocephalan parasite, Pomphorhynchus laevis, in two species of amphipods, Gammarus pulex and Gammarus roeseli in sympatry in the river Ouche (Burgundy, eastern France). There, G. pulex is a resident species, whereas G. roeseli is a recent coloniser. Both uninfected G. pulex and G. roeseli were strongly photophobic. although less so in the invading species. However, there was no significant difference in reaction to light between infected and uninfected G. roeseli, whereas infected G. pulex were strongly photophilic. We discuss our results in relation to the parasite's ability to manipulate invading host species, the possibility that resistant individuals have been selected during the invasion process, and the role that acanthocephalan parasites can play in shaping the structure of amphipod communities.

Acanthocephala↗
PubMed2003

Regulation of dendritic cell function through Toll-like receptors.

Higher animals establish host defense by orchestrating innate and adaptive immunity. This is mediated by professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can incorporate pathogens, produce a variety of cytokines, maturate, and present pathogen-derived peptides to T cells, thereby inducing T cell activation and differentiation. These responses are triggered by microbial recognition through type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist of ten members and each TLR is involved in recognizing a variety of microorganism-derived molecular structures. TLR ligands include cell wall components, proteins, nucleic acids, and synthetic chemical compounds, all of which can activate DCs as immune adjuvants. Each TLR can activate DCs in a similar, but distinct manner. For example, TLRs can be divided into subgroups according to their type I interferon (IFN) inducing ability. TLR2 cannot induce IFN-alpha or IFN-beta, but TLR4 can lead to IFN-beta production. Meanwhile, TLR3, TLR7, and TLR9 can induce both IFN-alpha and IFN-beta. Recent evidences suggest that cytoplamic adapters for TLRs are especially crucial for this functional heterogeneity. Clarifying how DC function is regulated by TLRs should provide us with critical information for manipulating the host defense against a variety of diseases.

Animals↗
PubMed2004

A genetic screen to isolate type III effectors translocated into pepper cells during Xanthomonas infection.

The bacterial pathogen Xanthomonas campestris pv. vesicatoria (Xcv) uses a type III secretion system (TTSS) to translocate effector proteins into host plant cells. The TTSS is required for Xcv colonization, yet the identity of many proteins translocated through this apparatus is not known. We used a genetic screen to functionally identify Xcv TTSS effectors. A transposon 5 (Tn5)-based transposon construct including the coding sequence for the Xcv AvrBs2 effector devoid of its TTSS signal was randomly inserted into the Xcv genome. Insertion of the avrBs2 reporter gene into Xcv genes coding for proteins containing a functional TTSS signal peptide resulted in the creation of chimeric TTSS effector::AvrBs2 fusion proteins. Xcv strains containing these fusions translocated the AvrBs2 reporter in a TTSS-dependent manner into resistant BS2 pepper cells during infection, activating the avrBs2-dependent hypersensitive response (HR). We isolated seven chimeric fusion proteins and designated the identified TTSS effectors as Xanthomonas outer proteins (Xops). Translocation of each Xop was confirmed by using the calmodulin-dependent adenylate cydase reporter assay. Three xop genes are Xanthomonas spp.-specific, whereas homologs for the rest are found in other phytopathogenic bacteria. XopF1 and XopF2 define an effector gene family in Xcv. XopN contains a eukaryotic protein fold repeat and is required for full Xcv pathogenicity in pepper and tomato. The translocated effectors identified in this work expand our knowledge of the diversity of proteins that Xcv uses to manipulate its hosts.

Bacterial Proteins↗
PubMed1998

Identification of putative cytoskeletal protein homologues in the protozoan host Hartmannella vermiformis as substrates for induced tyrosine phosphatase activity upon attachment to the Legionnaires' disease bacterium, Legionella pneumophila.

The Legionnaires' disease bacterium, Legionella pneumophila, is a facultative intracellular pathogen that invades and replicates within two evolutionarily distant hosts, free living protozoa and mammalian cells. Invasion and intracellular replication within protozoa are thought to be major factors in the transmission of Legionnaires' disease. We have recently reported the identification of a galactose/N-acetyl-D-galactosamine (Gal/GalNAc) lectin in the protozoan host Hartmannella vermiformis as a receptor for attachment and invasion by L. pneumophila (Venkataraman, C., B.J. Haack, S. Bondada, and Y.A. Kwaik. 1997. J. Exp. Med. 186:537-547). In this report, we extended our studies to the effects of bacterial attachment and invasion on the cytoskeletal proteins of H. vermiformis. We first identified the presence of many protozoan cytoskeletal proteins that were putative homologues to their mammalian counterparts, including actin, pp125(FAK), paxillin, and vinculin, all of which were basally tyrosine phosphorylated in resting H. vermiformis. In addition to L. pneumophila-induced tyrosine dephosphorylation of the lectin, bacterial attachment and invasion was associated with tyrosine dephosphorylation of paxillin, pp125(FAK), and vinculin, whereas actin was minimally affected. Inhibition of bacterial attachment to H. vermiformis by Gal or GalNAc monomers blocked bacteria-induced tyrosine dephosphorylation of detergent-insoluble proteins. In contrast, inhibition of bacterial invasion but not attachment failed to block bacteria-induced tyrosine dephosphorylation of H. vermiformis proteins. This was further supported by the observation that 10 mutants of L. pneumophila that were defective in invasion of H. vermiformis were capable of inducing tyrosine dephosphorylation of H. vermiformis proteins. Entry of L. pneumophila into H. vermiformis was predominantly mediated by noncoated receptor-mediated endocytosis (93%) but coiling phagocytosis was infrequently observed (7%). We conclude that attachment but not invasion by L. pneumophila into H. vermiformis was sufficient and essential to induce protein tyrosine dephosphorylation in H. vermiformis. These manipulations of host cell processes were associated with, or followed by, entry of the bacteria by a noncoated receptor-mediated endocytosis. A model for attachment and entry of L. pneumophila into H. vermiformis is proposed.

Actins↗
PubMed2025

Viral Enhancers Orchestrate Kaposi's Sarcoma-Associated Herpesvirus Transcription.

Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and other lymphoproliferative disorders, presents a delicate balance between host cell manipulation, and orchestrating its transcriptional repertoire. Like all herpes viruses, the virus can reside in latency, expressing only a handful of proteins or launch a lytic program that expresses over 80 proteins responsible for the generation and release of new virions. Enhancers, as their name suggests, can enhance the transcription rate from a promoter depending on the cellular environment and tissue. While the promoters in KSHV have been extensively studied, the enhancers were only recently identified. Here we will describe our current view on KSHV enhancers.

Herpesvirus 8, Human↗
PubMed2025

Translation of the downstream ORF from bicistronic mRNAs by human cells: Impact of codon usage and splicing in the upstream ORF.

Biochemistry textbooks describe eukaryotic mRNAs as monocistronic. However, increasing evidence reveals the widespread presence and translation of upstream open reading frames preceding the "main" ORF. DNA and RNA viruses infecting eukaryotes often produce polycistronic mRNAs and viruses have evolved multiple ways of manipulating the host's translation machinery. Here, we introduce an experimental model to study gene expression regulation from virus-like bicistronic mRNAs in human cells. The model consists of a short upstream ORF and a reporter downstream ORF encoding a fluorescent protein. We have engineered synonymous variants of the upstream ORF to explore large parameter space, including codon usage preferences, mRNA folding features, and splicing propensity. We show that human translation machinery can translate the downstream ORF from bicistronic mRNAs, albeit reporter protein levels are thousand times lower than those from the upstream ORF. Furthermore, synonymous recoding of the upstream ORF exclusively during elongation significantly influences its own translation efficiency, reveals cryptic splice signals, and modulates the probability of downstream ORF translation. Our results are consistent with a leaky scanning mechanism facilitating downstream ORF translation from bicistronic mRNAs in human cells, offering new insights into the role of upstream ORFs in translation regulation.

Humans↗
PubMed1991

Secretion of active truncated CD4 into Escherichia coli periplasm.

A truncated molecule containing the first 183 amino acid residues of the HIV-1 receptor, CD4, was made by periplasmic secretion in Escherichia coli. The signal sequence from the E. coli proteins OmpA, PhoA, or OmpF was fused to the truncated CD4, under the control of either the trp or the lac promoter. The processed material secreted into the periplasm reacted with monoclonal antibodies and exhibited binding activity to the HIV-1 envelope protein gp120. Not all of the processed product was recovered in the periplasm by osmotic shock, suggesting that either the material aggregated in the periplasm or, during secretion, the molecule assumed some transient conformation that interfered with its translocation across the inner membrane. A mutation in prlA (a gene involved in secretion) increased the level of processing, suggesting that secretion of a heterologous protein in E. coli can be optimized by manipulating the host secretion apparatus.

Amino Acid Sequence↗
PubMed1981

Effects of traumatic manipulations on grafts, sutures, and host arteries during vascular surgery procedures. Experiments on dogs.

Scanning electron microscopy was used to diagnose incidents of trauma and the pattern of healing following surgical implantation of microporous blood vessel substitutes. Vascular reconstruction procedures using autogenous or synthetic prosthetic material inflict damage to the adjacent tissues as well as the prosthesis. This affects the thrombotic behavior and healing pattern of the area. The prognosis for long-term success are, as a consequence, directly influenced. Various vessel-occluding devices were evaluated in canine models with respect to their ability to damage blood vessels at the clamped site. The impact of suture needles on tissues and prosthetic materials was also considered. Of the various vessel-clamping devices which are commercially available, those which have elastomeric shields on the clamping components were found to be most satisfactory. The development of less traumatic surgical devices is discussed with the aim of further reducing surgical trauma.

Animals↗
PubMed2003

Wasp uses venom cocktail to manipulate the behavior of its cockroach prey.

The sting of the parasitoid wasp Ampulex compressa is unusual, as it induces a transient paralysis of the front legs followed by grooming behavior and then by a long-term hypokinesia of its cockroach prey. Because the wasp's goal is to provide a living meal for its newborn larva, the behavioral changes in the prey are brought about by manipulating the host behavior in a way beneficial to the wasp and its offspring. To this end, the wasp injects its venom cocktail with two consecutive stings directly into the host's central nervous system. The first sting in the thorax causes a transient front leg paralysis lasting a few minutes. This paralysis is due to the presence of a venom component that induces a postsynaptic block of central cholinergic synaptic transmission. Following the head sting, dopamine identified in the venom appears to induce 30 min of intense grooming. During the long-term hypokinesia that follows the grooming, specific behaviors of the prey are inhibited while others are unaffected. We propose that the venom represses the activity of head ganglia neurons thereby removing the descending excitatory drive to the thoracic neurons.

Animals↗
PubMed2005

NOR activity and repeat sequences of the paternal sex ratio chromosome of the parasitoid wasp Trichogramma kaykai.

Part of the male population of the wasp Trichogramma kaykai carries a B chromosome that manipulates its host sex ratio in favour of males. The only known repeat on this paternal sex ratio (PSR) chromosome is the 45S rDNA, which includes here five different internal transcribed spacer 2 (ITS2) sequences. In this report, we describe that only part of these ITS2 sequences is transcribed. The absence of transcription of some ITS2 sequences might explain the presence of multiple ITS2 sequences on the PSR chromosome since homogenization of rDNA spacers is thought to occur only in transcribed regions. Analysis of the only other known tandem repeat in Trichogramma, the EcoRI repeat, showed that it is absent from the PSR chromosome, and that the T. kaykai EcoRI repeat has 98 and 77% DNA sequence homology with the T. deion and T. brassicae EcoRI repeats, respectively. The size of the PSR chromosome measures 9 Mbp and is equal to 3.9% of the haploid T. kaykai genome. Finally, fluorescent in situ hybridization with a pool of high and moderate repetitive T. kaykai DNA (C0t-50) revealed only a very few major tandem repeats on the Trichogramma genome and only 45S rDNA on the PSR chromosome.

Animals↗
PubMed2001

Inhibition of apoptosis by primary isolates of herpes simplex virus.

HSV-1 inhibits apoptosis of the infected cell, presumably to increase viral yield. Weaker anti-apoptotic activity was previously reported in laboratory-adapted HSV-2, but not in two low-passage clinical HSV-2 isolates, suggesting that the anti-apoptotic effect might result from adaptation to laboratory growth. We therefore assembled a large panel of clinical strains of HSV-1 and HSV-2. Clinical and laboratory strains of HSV-1 strongly inhibited apoptosis of Jurkat cells, as determined by morphologic change or caspase activation, while clinical HSV-2 strains showed no inhibitory activity in Jurkat cells. These findings suggest fundamental differences between HSV-1 and HSV-2 in their manipulation of host cell apoptosis.

Animals↗
PubMed1990

Plasmodium yoelii: comparative antimalarial activities of dietary fish oils and fish oil concentrates in vitamin E-deficient mice.

Feeding vitamin E-deficient diets containing either fish oils such as menhaden, salmon, or anchovy oil or fish oil concentrates based on n-3 ethyl esters or free fatty acids protected mice against Plasmodium yoelii as indicated by decreased parasitemia and improved survival. The fish oil concentrates depressed plasma tocopherol levels more strongly in vitamin E-supplemented mice than the menhaden oil. The free fatty acid concentrate appeared to suppress parasitemia in vitamin E-deficient mice better than the menhaden oil, although ultimate survival was similar in both groups. Dietary manipulation of host antioxidant status offers promise as a possible means of malaria control.

Animals↗
PubMed1989

Immunology of central nervous system tumors.

With progress in cellular immunology and the development of hybridoma technology, the idea of manipulating host-tumor immune interactions to improve the prognosis of brain tumors has aroused renewed interest. Although no brain tumor-specific antigens have been found, and in spite of the wide antigenic heterogeneity of brain tumor cells, some monoclonal antibodies possessing restricted specificity have been isolated and their potential clinical applications investigated. One of the most pronounced changes in the cellular immune responses of brain tumor patients is a profound depression of the T4-helper lymphocytes. Clinical and laboratory trials are under way to assess the ability of lymphokines, such as gamma-interferon or interleukin-2, to restore immunologic competence in these patients and potentiate a specific anti-tumor immunologic response. Recent work suggests that the endothelium-astrocyte complex may have a pivotal role in assisting the escape of brain tumors from the host's immunologic responses, since it is responsible for the intracerebral sequestration of antigens and local anti-tumor responses. In this review, the data on the antigenic properties of central nervous system tumors and the host's humoral and cellular immune responses to them are analyzed and potential immunologic therapies are discussed.

Antibody Formation↗
PubMed1994

Allogeneic grafts of fetal dopamine neurons: behavioral indices of immunological interactions.

Fetal central nervous system transplants to the adult brain have been utilized to understand brain connectivity and as replacement therapy in Parkinson's disease (PD). Here we use fetal brain allografting in the rat unilaterally depleted of dopamine, a unilateral model of PD, and apomorphine-induced rotations as an index of graft functional status while peripherally manipulating the host's alloimmune status. This system allows the investigator to examine, dynamically, host-allograft interactions in the brain under differing states of alloimmunoreactivity without the need to biopsy or sacrifice the animal. In addition to this novel application, we established that brain allografts are differentially susceptible to immunologic attack depending upon the graft's duration of residence in the host brain. Increasing residence time increases graft 'rejectability' to peripheral allosensitization. Passive immunization also sensitizes the host to subsequent graft rejection. Lastly, simple host alloimmunocompetence is necessary but not sufficient to cause fetal graft 'rejection', defined as a return of apomorphine-induced rotations.

Animals↗