The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Daniel F Hoft - One of the best experts on this subject based on the ideXlab platform.
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th17 cells are more protective than th1 cells against the Intracellular Parasite trypanosoma cruzi
PLOS Pathogens, 2016Co-Authors: Catherine W Cai, Jennifer R Blase, Xiuli Zhang, Christopher S Eickhoff, Daniel F HoftAbstract:Th17 cells are a subset of CD4+ T cells known to play a central role in the pathogenesis of many autoimmune diseases, as well as in the defense against some extracellular bacteria and fungi. However, Th17 cells are not believed to have a significant function against Intracellular infections. In contrast to this paradigm, we have discovered that Th17 cells provide robust protection against Trypanosoma cruzi, the Intracellular protozoan Parasite that causes Chagas disease. Th17 cells confer significantly stronger protection against T. cruzi-related mortality than even Th1 cells, traditionally thought to be the CD4+ T cell subset most important for immunity to T. cruzi and other Intracellular microorganisms. Mechanistically, Th17 cells can directly protect infected cells through the IL-17A-dependent induction of NADPH oxidase, involved in the phagocyte respiratory burst response, and provide indirect help through IL-21-dependent activation of CD8+ T cells. The discovery of these novel Th17 cell-mediated direct protective and indirect helper effects important for Intracellular immunity highlights the diversity of Th17 cell roles, and increases understanding of protective T. cruzi immunity, aiding the development of therapeutics and vaccines for Chagas disease.
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th17 cells are more protective than th1 cells against the Intracellular Parasite trypanosoma cruzi
Journal of Immunology, 2016Co-Authors: Catherine W Cai, Jennifer R Blase, Christopher S Eickhoff, Daniel F HoftAbstract:Th1 cells are considered the major CD4 + T helper subset responsible for the control of Intracellular pathogens, including Trypanosoma cruzi, the protozoan Parasite of Chagas disease. Th17 cells are known for their involvement in autoimmunity and the defense against some extracellular organisms, but are generally not believed to have a significant function during Intracellular infections. In contrast, we show that Th17 cells are highly protective against the Intracellular pathogen T. cruzi . We reconstituted RAG KO mice lacking endogenous T cells with polyclonal CD8 + T cells and Parasite-specific Th1 or Th17 cells, generated from novel T cell receptor transgenic mice recently developed by us. After adoptive cell transfer, recipients were infected with a normally lethal dose of T. cruzi . Th17 cells impressively protected 100% of mice from mortality long-term, while Th1 cells protected only 38%. Transfer of Th17 cells alone failed to protect, implicating helper effects on CD8 + T cells as the basic mechanism of Th17-mediated Intracellular immunity. We confirmed this using in vitro assays, and discovered that Th17 cells help activate CD8 + T cells through IL-21 secretion, indicating a protective mechanism surprisingly independent of the main Th17 cytokine IL-17A. In vivo, co-transfer of IL-21R knock-out CD8 + T cells with Th17 cells failed to protect mice, confirming the importance of IL-21 signaling. In summary, our data define an important new role for Th17 cells in the defense against a major Intracellular human pathogen and define novel mechanisms of Th17 cell effects. This work increases our understanding of the protective immune interactions in T. cruzi infection, and more broadly, illuminates the growing diversity of Th17 cell roles.
Boris Striepen - One of the best experts on this subject based on the ideXlab platform.
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the biology of the intestinal Intracellular Parasite cryptosporidium
Cell Host & Microbe, 2020Co-Authors: Amandine Guerin, Boris StriepenAbstract:Summary Cryptosporidium emerged as a leading global cause of severe diarrheal disease in children. The Parasite occupies a unique Intracellular niche at the brush border of intestinal epithelial cells, where it undergoes a complex sexual life cycle. How this life cycle unfolds and how host and Parasite interact remain largely to be discovered. A series of technical advances now offer genetic and immunological tools for mechanistic investigation of the Parasite. Here we introduce the pathogen and disease and highlight important questions to tackle onward. We invite scientists to consider this versatile Parasite model to probe the biology and immunology of the intestine.
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the Intracellular Parasite toxoplasma gondii depends on the synthesis of long chain and very long chain unsaturated fatty acids not supplied by the host cell
Molecular Microbiology, 2015Co-Authors: S. Ramakrishnan, Malcolm J. Mcconville, Melissa D. Docampo, James I. Macrae, Julie E. Ralton, Thusitha W. T. Rupasinghe, Boris StriepenAbstract:Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these Parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for Parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed Intracellular Parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the Parasite and availability of specific fatty acids in the host cell that the Parasite has to close using a dedicated synthesis and modification pathway.
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The Intracellular Parasite Toxoplasma gondii depends on the synthesis of long‐chain and very long‐chain unsaturated fatty acids not supplied by the host cell
Molecular microbiology, 2015Co-Authors: S. Ramakrishnan, Malcolm J. Mcconville, Melissa D. Docampo, James I. Macrae, Julie E. Ralton, Thusitha W. T. Rupasinghe, Boris StriepenAbstract:Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these Parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for Parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed Intracellular Parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the Parasite and availability of specific fatty acids in the host cell that the Parasite has to close using a dedicated synthesis and modification pathway.
Malcolm J. Mcconville - One of the best experts on this subject based on the ideXlab platform.
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Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival.
mBio, 2020Co-Authors: Geo Semini, Mf Sernee, Daniel Paape, Martin Blume, Diego Peres-alonso, Sébastien Calvignac-spencer, Jörg Döllinger, Stefan Jehle, Eleanor C Saunders, Malcolm J. McconvilleAbstract:Leishmania spp. are protozoan Parasites that cause a spectrum of important diseases in humans. These Parasites develop as extracellular promastigotes in the digestive tract of their insect vectors and as obligate Intracellular amastigotes that infect macrophages and other phagocytic cells in their vertebrate hosts. Promastigote-to-amastigote differentiation is associated with marked changes in metabolism, including the upregulation of enzymes involved in fatty acid β-oxidation, which may reflect adaptation to the Intracellular niche. Here, we have investigated the function of one of these enzymes, a putative 2,4-dienoyl-coenzyme A (CoA) reductase (DECR), which is specifically required for the β-oxidation of polyunsaturated fatty acids. The Leishmania DECR shows close homology to bacterial DECR proteins, suggesting that it was acquired by lateral gene transfer. It is present in other trypanosomatids that have obligate Intracellular stages (i.e., Trypanosoma cruzi and Angomonas) but is absent from dixenous Parasites with an exclusively extracellular lifestyle (i.e., Trypanosoma brucei). A DECR-green fluorescent protein (GFP) fusion protein was localized to the mitochondrion in both promastigote and amastigote stages, and the levels of expression increased in the latter stages. A Leishmania major Δdecr null mutant was unable to catabolize unsaturated fatty acids and accumulated the intermediate 2,4-decadienoyl-CoA, confirming DECR's role in β-oxidation. Strikingly, the L. major Δdecr mutant was unable to survive in macrophages and was avirulent in BALB/c mice. These findings suggest that β-oxidation of polyunsaturated fatty acids is essential for Intracellular Parasite survival and that the bacterial origin of key enzymes in this pathway could be exploited in developing new therapies.IMPORTANCE The Trypanosomatidae are protozoan Parasites that infect insects, plants, and animals and have evolved complex monoxenous (single host) and dixenous (two hosts) lifestyles. A number of species of Trypanosomatidae, including Leishmania spp., have evolved the capacity to survive within Intracellular niches in vertebrate hosts. The adaptations, metabolic and other, that are associated with development of Intracellular lifestyles remain poorly defined. We show that genomes of Leishmania and Trypanosomatidae that can survive Intracellularly encode a 2,4-dienoyl-CoA reductase that is involved in catabolism of a subclass of fatty acids. The trypanosomatid enzyme shows closest similarity to the corresponding bacterial enzymes and is located in the mitochondrion and essential for Intracellular growth of Leishmania The findings suggest that acquisition of this gene by lateral gene transfer from bacteria by ancestral monoxenous Trypanosomatidae likely contributed to the development of a dixenous lifestyle of these Parasites.
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the Intracellular Parasite toxoplasma gondii depends on the synthesis of long chain and very long chain unsaturated fatty acids not supplied by the host cell
Molecular Microbiology, 2015Co-Authors: S. Ramakrishnan, Malcolm J. Mcconville, Melissa D. Docampo, James I. Macrae, Julie E. Ralton, Thusitha W. T. Rupasinghe, Boris StriepenAbstract:Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these Parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for Parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed Intracellular Parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the Parasite and availability of specific fatty acids in the host cell that the Parasite has to close using a dedicated synthesis and modification pathway.
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The Intracellular Parasite Toxoplasma gondii depends on the synthesis of long‐chain and very long‐chain unsaturated fatty acids not supplied by the host cell
Molecular microbiology, 2015Co-Authors: S. Ramakrishnan, Malcolm J. Mcconville, Melissa D. Docampo, James I. Macrae, Julie E. Ralton, Thusitha W. T. Rupasinghe, Boris StriepenAbstract:Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these Parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for Parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed Intracellular Parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the Parasite and availability of specific fatty acids in the host cell that the Parasite has to close using a dedicated synthesis and modification pathway.
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using fat to turbo charge Intracellular Parasite growth
Cell Host & Microbe, 2014Co-Authors: Malcolm J. McconvilleAbstract:Early during infection, the malaria Parasite invades liver cells and undergoes robust replication, generating thousands of new Parasites within days. In this issue of Cell Host & Microbe, Itoe et al. (2014) show that Parasite replication in the liver depends on the synthesis of host bulk phospholipids, which are incorporated into the expanding Parasite and surrounding vacuolar membranes.
Catherine W Cai - One of the best experts on this subject based on the ideXlab platform.
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th17 cells are more protective than th1 cells against the Intracellular Parasite trypanosoma cruzi
PLOS Pathogens, 2016Co-Authors: Catherine W Cai, Jennifer R Blase, Xiuli Zhang, Christopher S Eickhoff, Daniel F HoftAbstract:Th17 cells are a subset of CD4+ T cells known to play a central role in the pathogenesis of many autoimmune diseases, as well as in the defense against some extracellular bacteria and fungi. However, Th17 cells are not believed to have a significant function against Intracellular infections. In contrast to this paradigm, we have discovered that Th17 cells provide robust protection against Trypanosoma cruzi, the Intracellular protozoan Parasite that causes Chagas disease. Th17 cells confer significantly stronger protection against T. cruzi-related mortality than even Th1 cells, traditionally thought to be the CD4+ T cell subset most important for immunity to T. cruzi and other Intracellular microorganisms. Mechanistically, Th17 cells can directly protect infected cells through the IL-17A-dependent induction of NADPH oxidase, involved in the phagocyte respiratory burst response, and provide indirect help through IL-21-dependent activation of CD8+ T cells. The discovery of these novel Th17 cell-mediated direct protective and indirect helper effects important for Intracellular immunity highlights the diversity of Th17 cell roles, and increases understanding of protective T. cruzi immunity, aiding the development of therapeutics and vaccines for Chagas disease.
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th17 cells are more protective than th1 cells against the Intracellular Parasite trypanosoma cruzi
Journal of Immunology, 2016Co-Authors: Catherine W Cai, Jennifer R Blase, Christopher S Eickhoff, Daniel F HoftAbstract:Th1 cells are considered the major CD4 + T helper subset responsible for the control of Intracellular pathogens, including Trypanosoma cruzi, the protozoan Parasite of Chagas disease. Th17 cells are known for their involvement in autoimmunity and the defense against some extracellular organisms, but are generally not believed to have a significant function during Intracellular infections. In contrast, we show that Th17 cells are highly protective against the Intracellular pathogen T. cruzi . We reconstituted RAG KO mice lacking endogenous T cells with polyclonal CD8 + T cells and Parasite-specific Th1 or Th17 cells, generated from novel T cell receptor transgenic mice recently developed by us. After adoptive cell transfer, recipients were infected with a normally lethal dose of T. cruzi . Th17 cells impressively protected 100% of mice from mortality long-term, while Th1 cells protected only 38%. Transfer of Th17 cells alone failed to protect, implicating helper effects on CD8 + T cells as the basic mechanism of Th17-mediated Intracellular immunity. We confirmed this using in vitro assays, and discovered that Th17 cells help activate CD8 + T cells through IL-21 secretion, indicating a protective mechanism surprisingly independent of the main Th17 cytokine IL-17A. In vivo, co-transfer of IL-21R knock-out CD8 + T cells with Th17 cells failed to protect mice, confirming the importance of IL-21 signaling. In summary, our data define an important new role for Th17 cells in the defense against a major Intracellular human pathogen and define novel mechanisms of Th17 cell effects. This work increases our understanding of the protective immune interactions in T. cruzi infection, and more broadly, illuminates the growing diversity of Th17 cell roles.
Dirk A. E. Dobbelaere - One of the best experts on this subject based on the ideXlab platform.
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Multiphoton imaging of ultrashort pulse laser ablation in the Intracellular Parasite Theileria
Journal of biomedical optics, 2008Co-Authors: Patrick Stoller, Dominik Marti, Jacqueline Schmuckli-maurer, Dirk A. E. Dobbelaere, Martin FrenzAbstract:Theileria annulata is an Intracellular Parasite that infects and transforms bovine leukocytes, inducing continuous proliferation of its host cell both in vivo and in vitro. Theileria-infected cells can easily be propagated in the laboratory and serve as a good model for laser ablation studies. Using single pulses from an amplified ultrashort pulse laser system, we developed a technique to introduce submicrometer holes in the plasma membrane of the Intracellular schizont stage of Theileria annulata. This was achieved without compromising either the viability of the organisms or that of the host cell that harbors the Parasite in its cytoplasm. Multiphoton microscopy was used to generate image stacks of the Parasite before and after ablation. The high axial resolution allowed precise selection of the region of the membrane that was ablated. It also allowed observation of the size of the holes generated (in fixed, stained cells) and determination of the structural changes in the Parasite resulting from the laser pulses (in living cells in vitro). This technique opens a new possibility for the transfection of Theileria or delivery of molecules to the schizont that may prove useful in the study of this special host-Parasite relationship.
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The Intracellular Parasite Theileria parva protects infected T cells from apoptosis
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Volker Heussler, Joel Machado, Paula Fernandez, Catherine Botteron, Chao-guang Chen, Martin J. Pearse, Dirk A. E. DobbelaereAbstract:Parasites have evolved a plethora of strategies to ensure their survival. The Intracellular Parasite Theileria parva secures its propagation and spreads through the infected animal by infecting and transforming T cells, inducing their continuous proliferation and rendering them metastatic. In previous work, we have shown that the Parasite induces constitutive activation of the transcription factor NF-kappaB, by inducing the constitutive degradation of its cytoplasmic inhibitors. The biological significance of NF-kappaB activation in T. parva-infected cells, however, has not yet been defined. Cells that have been transformed by viruses or oncogenes can persist only if they manage to avoid destruction by the apoptotic mechanisms that are activated on transformation and that contribute to maintain cellular homeostasis. We now demonstrate that Parasite-induced NF-kappaB activation plays a crucial role in the survival of T. parva-transformed T cells by conveying protection against an apoptotic signal that accompanies Parasite-mediated transformation. Consequently, inhibition of NF-kappaB nuclear translocation and the expression of dominant negative mutant forms of components of the NF-kappaB activation pathway, such as IkappaBalpha or p65, prompt rapid apoptosis of T. parva-transformed T cells. Our findings offer important insights into Parasite survival strategies and demonstrate that Parasite-induced constitutive NF-kappaB activation is an essential step in maintaining the transformed phenotype of the infected cells.
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jun nh2 terminal kinase is constitutively activated in t cells transformed by the Intracellular Parasite theileria parva
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Yves Galley, Margarete Eichhorn, Gerry Hagens, Isabel Glaser, W M Davis, Dirk A. E. DobbelaereAbstract:When T cells become infected by the Parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the Parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a Parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCRζ or CD3ɛ chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for Parasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathways to induce continuous proliferation.
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Constitutive IL-2 mRNA expression in lymphocytes, infected with the Intracellular Parasite Theileria parva.
Journal of immunology (Baltimore Md. : 1950), 1992Co-Authors: Volker Heussler, Richard O. Williams, Margarete Eichhorn, Raymond Reeves, Nancy S. Magnuson, Dirk A. E. DobbelaereAbstract:Theileria parva-infected lymphoblastoid cell lines of T or B cell origin were examined for IL-2 mRNA expression. T. parva-infected T cell lines could be of the CD4-CD8-, CD4+CD8-, CD4-CD8+, or CD4+CD8+ phenotype and express alpha beta or gamma delta TCR. By Northern blot analysis and amplification by the polymerase chain reaction, IL-2 mRNA could be detected in all T. parva-infected cell lines tested. IL-2 mRNA expression was also shown to be dependent on the continuous presence of the Parasite in the host cell cytoplasm, because elimination of the Parasite by treatment of T. parva-infected cell cultures with the theilericidal drug BW720c resulted in the disappearance of detectable IL-2 mRNA. The effect of anti-IL-2 antibodies on the proliferation of T. parva-infected cells was also tested. Inhibition experiments suggest that although IL-2 mRNA can be detected in all cell lines tested, not all T. parva-infected cell lines are dependent on IL-2 for their proliferation. Our data provide the first example for the constitutive expression of IL-2 mRNA in T and B cells caused by infection with an Intracellular Parasite.
