Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin
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{"title"=>"Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin", "type"=>"journal", "authors"=>[{"first_name"=>"Zhu Hong", "last_name"=>"Li", "scopus_author_id"=>"7409083059"}, {"first_name"=>"Srinivasan", "last_name"=>"Ramakrishnan", "scopus_author_id"=>"54980974200"}, {"first_name"=>"Boris", "last_name"=>"Striepen", "scopus_author_id"=>"7003447882"}, {"first_name"=>"Silvia N.J.", "last_name"=>"Moreno", "scopus_author_id"=>"7203036530"}], "year"=>2013, "source"=>"PLoS Pathogens", "identifiers"=>{"scopus"=>"2-s2.0-84887301097", "sgr"=>"84887301097", "issn"=>"15537366", "doi"=>"10.1371/journal.ppat.1003665", "pmid"=>"24146616", "isbn"=>"1553-7374", "pui"=>"370218058"}, "id"=>"ef64cdfd-060a-378f-936b-973b9465e195", "abstract"=>"Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite Toxoplasma gondii to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, T. gondii expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize T. gondii null mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites.", "link"=>"http://www.mendeley.com/research/toxoplasma-gondii-relies-both-host-parasite-isoprenoids-rendered-sensitive-atorvastatin", "reader_count"=>29, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>5, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>5, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>6, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>12, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>2}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1245586"], "description"=>"<p><i>A</i>, Cosmid strategy used to delete the <i>TgFPPS</i> gene. CAT: chloramphenicol acetyl transferase gene used for <i>T. gondii</i> selection. Restriction enzyme SalI cuts the <i>TgFPPS</i> genomic DNA three times and once the <i>TgFPPS</i> cDNA. P1 indicates the probe used for Southern blot analysis. <b><i>B</i></b><b>,</b> Southern blot analysis with probe P1 shows deletion of the endogenous <i>TgFPPS</i> gene and its appearance in the complemented tachyzoites. <i>Δfpps</i>: <i>TgFPPS null</i> mutant, <i>Δfpps-cm1</i> and <i>Δfpps-cm2</i>: <i>TgFPPS null</i> mutant complemented with the <i>TgFPPS</i> gene (clone 1 and 2). <b><i>C</i></b><b>,</b> Western blot analysis showing the absence of TgFPPS in the <i>Δfpps</i> mutants and its presence in the parental <i>Δku80</i>, <i>Δfpps-cm1</i> and <i>Δfpps-cm2</i> tachyzoites. <b><i>D</i></b><b>,</b> Growth of <i>Δku80, Δfpps and Δfpps-cm (clone 1)</i> in fibroblasts followed by red fluorescence as in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003665#ppat.1003665-Nair1\" target=\"_blank\">[7]</a>. A standard curve was developed for fluorescence vs. number of parasites. <b><i>E</i></b><b>,</b> Growth of <i>Δku80, Δfpps and Δfpps-cm</i> in macrophages J744. <b><i>F</i></b><b>,</b> Growth competition assay in fibroblasts (<i>Fib, black</i>) or macrophages (<i>Mac, blue</i>). 5% of <i>Δku80</i> or <i>Δfpps-cm</i> (both of them expressing rfp) were mixed with 95% of <i>Δfpps</i> parasites. The fluorescence level at each passage follows growth of parental or complemented cells. Both, <i>Δku80</i> or <i>Δfpps-cm</i> can overgrow <i>Δfpps</i> parasites in macrophages (see increasing red fluorescence only in macrophages). <b><i>G</i></b><b>,</b> Fluorescence microscopy of parental tachyzoites expressing tandem tomato RFP protein and grown in macrophages (<i>upper panels</i>) or fibroblasts (<i>lower panels</i>) showing their predominant growth in macrophages and only a small number of fluorescent parasites when grown in fibroblasts. Data in <b><i>D</i></b>, <b><i>E,</i></b><i> </i><b><i>F</i></b> represent means ± SD of n = 3. The Y axis of <b><i>D</i></b>, <b><i>E</i></b> and <b><i>F</i></b> indicates % parasites considering 100% the number of parasites of the <i>Δku80</i> strain at day 5.</p>", "links"=>[], "tags"=>["stressful"], "article_id"=>826257, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TgFPPS_is_essential_for_growth_of_T_gondii_under_stressful_conditions_/826257", "title"=>"<i>TgFPPS</i> is essential for growth of <i>T. gondii</i> under stressful conditions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245588"], "description"=>"<p><i>A</i>, Freshly egressed parasites were filtered, collected, and resuspended in DMEM medium. These parasites were incubated in DMEM medium at 37°C for 0.5 hs before allowing them to infect hTERT fibroblasts. Plaques were counted as detailed under <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003665#s4\" target=\"_blank\">Materials and Methods</a>. The data plotted are from 3 independent experiments. The number of plaques for the <i>Δfpps</i> and for the <i>Δfpps-cm</i> are normalized considering the number of plaques for the parental cells <i>Δku80</i> as 100% (*<i>Δfpps vs Δku80</i>, P = 0.002, *<i>Δfpps vs Δfpps-cm:</i> P = 0.08, not significant) <b><i>B</i></b><b>,</b> ATP levels of recently released parasites (0 hour) or parasites incubated in buffer simulating extracellular ionic conditions for one hour (1 hour). The Y-axis indicates % ATP level considering the value obtained from the <i>Δku80</i> strain at time 0 as 100%. Results are expressed as means ± S.D. of n = 3. Other experimental conditions are under <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003665#s4\" target=\"_blank\">Materials and Methods</a>. (At 1 hour: <i>*Δfpps vs Δku80</i>, P = 0.002, <i>*Δfpps vs Δfpps-cm:</i> P = 0.0004) <b><i>C</i></b><b>,</b> Fluorescence analysis of <i>Δku80</i> and <i>Δfpps</i> tachyzoites stained with JC1, showing decrease in mitochondrial membrane potential of <i>Δfpps</i> tachyzoites (note the decrease in red fluorescence).</p>", "links"=>[], "tags"=>["knockout", "parasites", "mitochondrial"], "article_id"=>826258, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TgFPPS_knockout_parasites_have_a_mitochondrial_defect_/826258", "title"=>"<i>TgFPPS</i> knockout parasites have a mitochondrial defect.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245589"], "description"=>"<p><i>A</i>, <i>T. gondii</i>-infected fibroblasts were labeled with <sup>14</sup>C -glucose. Isoprenoids were extracted from purified tachyzoites and analyzed by thin layer chromatography (TLC); <b><i>B</i></b><b>,</b> Fibroblasts were labeled with <sup>14</sup>C-glucose for 2 days and infected with <i>T. gondii</i> after washing with non-radiolabeled medium. Tachyzoites were collected after growing without <sup>14</sup>C-glucose and purified for further extraction of their isoprenoids as described under <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003665#s4\" target=\"_blank\">Materials and Methods</a>. Isoprenoids were hydrolyzed to their corresponding alcohols and analyzed by TLC using a previously described system <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003665#ppat.1003665-Ling1\" target=\"_blank\">[8]</a>. Ori indicates the origin, FOH, farnesol, GGOH, geranylgeraniol, 25C and 35C are isoprenoid products that run in this system as isoprenoids with that number of carbons. The length of the isoprenoid products was calculated from a standard curve made using known isoprenoid standards and measuring the length of the run for each compound. This a is representative TLC from more than 3 independent experiments with similar results. <b><i>C</i></b><b>,</b> Calculation of the ratio between the cpm obtained for the 35C and GGOH spots obtained in <b><i>A</i></b><b>,</b> using a phosphoroimager and multiplied by 100. <b><i>D</i></b><b>,</b> Same as in C for the TLC in <b><i>B</i></b>.</p>", "links"=>[], "tags"=>["salvage", "isoprenoid", "intermediates"], "article_id"=>826259, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_T_gondii_can_salvage_isoprenoid_intermediates_from_its_host_/826259", "title"=>"<i>T. gondii</i> can salvage isoprenoid intermediates from its host.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245590"], "description"=>"<p><i>A</i>, Growth inhibition of <i>Δku80</i>, <i>Δfpps</i> and <i>Δfpps-cm</i> tachyzoites by atorvastatin. <b><i>B</i></b><b>, </b><i>Δku80</i>, <i>Δfpps</i> and <i>Δfpps-cm</i> tachyzoites were cultured in the presence of 13 µM atorvastatin. Where indicated (<i>Δfpps</i>+GGOH) geranylgeraniol (1 µM) was added to the culture medium. <b><i>C</i></b><b>,</b> Growth inhibition of <i>Δku80</i>, <i>Δfpps</i> and <i>Δfpps-cm</i> tachyzoites by the squalene synthase inhibitor WC-9. <b><i>D</i></b><b>,</b> Growth inhibition of the <i>T. gondii</i> FPPS/FPPSi, ΔFPPS/FPPSi and ΔFPPS/FPPSi+ATc in the presence of different concentrations of mevastatin. <b><i>E</i></b><b>,</b> FPPS/FPPSi, ΔFPPS/FPPSi and ΔFPPS/FPPSi+ATc were cultured in the presence of 5 µM mevastatin. Where indicated (ΔFPPS/FPPSi+ATc+GGOH) geranylgeraniol (1 µM) was added to the culture medium. The number of parasites at day 5 in the absence of inhibitor is considered as 100%. Results are expressed as means ± SD of n = 3.</p>", "links"=>[], "tags"=>["parasite", "isoprenoid"], "article_id"=>826260, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_the_host_and_parasite_isoprenoid_pathways_/826260", "title"=>"Inhibition of the host and parasite isoprenoid pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245592"], "description"=>"<p><b><i>A</i></b><b>,</b> Atorvastatin treatment of mice infected with the RH strain. 20 RH tachyzoites were injected i.p. into Swiss Webster mice. Atorvastatin was given i.p. daily starting 6 hours after infection for 15 days. Results are the summary of 4 independent experiments. <b><i>B</i></b><b>,</b> Atorvastatin can cure mice infected with a lethal dose of <i>Δfpps</i> parasites. 10 <i>Δku80</i> or <i>Δfpps</i> tachyzoites were inoculated (i.p.) into Swiss Webster mouse. Atorvastatin (20 mg/kg/day) started 6 hours after infection for 10 days. Results are from 3 independent experiments using 10 mice for each group. <b><i>C</i></b><b>,</b> Atorvastatin cures a lethal infection with ΔFPPS/FPPSi parasites. Balb/c mice were infected with 100,000 fresh tachyzoites (i.p.) of FPPS/FPPSi (<i>black lines</i>) or ΔFPPS/FPPSi (<i>red lines</i>). Atorvastatin protect mice against death if the infection with ΔFPPS/FPPSi is followed by the administration of 0.2 µg/ml anhydrotetracyclin ATc to suppress the expression of the extra copy of TgFPPS (<i>red dashed line</i>) (80% mice survive). Only 20% of mice infected with FPPS/FPPSi parasites survive if treated with atorvastatin (<i>black dotted line</i>). The results shown are from 2 independent experiments (10 mice each group). Treatment with atorvastatin (20 mg/kg×day, i.p.) was started 6 hours after infection for 10 days for the groups indicated. Note that graphs start at day 1 but infection is done on day 0.</p>", "links"=>[], "tags"=>["atorvastatin", "mice", "infected"], "article_id"=>826261, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_atorvastatin_in_mice_infected_with_T_gondii_/826261", "title"=>"Effect of atorvastatin in mice infected with <i>T. gondii.</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245593"], "description"=>"<p><i>A</i>, Isobolograms of the interaction of atorvastatin and zoledronate. Axes are all normalized IC<sub>50</sub>s. Data are from 3 independent experiments. The dotted line indicates the hypothetical additive curve. <b><i>B</i></b><b>,</b> Growth curve of tachyzoites expressing GlpT in the presence of 50 µM atorvastatin and 0.78 µM fosmidomycin. Results are expressed as means ± S.D. of n = 3.</p>", "links"=>[], "tags"=>["atorvastatin", "inhibitor", "tgfpps", "doxp"], "article_id"=>826262, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_of_atorvastatin_with_an_inhibitor_of_the_TgFPPS_and_with_an_inhibitor_of_the_DOXP_pathway_/826262", "title"=>"Combination of atorvastatin with an inhibitor of the TgFPPS and with an inhibitor of the DOXP pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245594"], "description"=>"<p>The cartoon shows isoprenoid metabolites synthesized by <i>Toxoplasma gondii</i> tachyzoites (pink) and host (beige) and their interaction. The DOXP pathway enzymes localize to the parasite apicoplast (green). The mevalonate pathway enzymes are only present in the host. Green arrows show metabolites imported from the host as demonstrated in this work. The parasite enzyme TgFPPS synthesizes both FPP and GGPP while the host uses two enzymes (FPPS and GGPPS) to make the same metabolites. Enzymes and their known inhibitors are indicated. G3P: glyceraldehyde 3-phosphate; DMAPP: dimethyl allyl diphosphate; IPP: isopentenyl diphosphate; GPP: geranyl diphosphate; FPP: farnesyl diphosphate; GGPP: geranylgeranyl diphosphate; N-BP: nitrogen bisphosphonates; Alkyl-BP: alkyl bisphosphonates; Fos: fosmidomycin.</p>", "links"=>[], "tags"=>["isoprenoid"], "article_id"=>826263, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Toxoplasma_gondii_and_host_isoprenoid_intermediates_/826263", "title"=>"<i>Toxoplasma gondii</i> and host isoprenoid intermediates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-17 02:46:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1245597", "https://ndownloader.figshare.com/files/1245598", "https://ndownloader.figshare.com/files/1245599", "https://ndownloader.figshare.com/files/1245600", "https://ndownloader.figshare.com/files/1245601"], "description"=>"<div><p>Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite <i>Toxoplasma gondii</i> to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, <i>T. gondii</i> expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize <i>T. gondii null</i> mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites.</p></div>", "links"=>[], "tags"=>["relies", "parasite", "isoprenoids", "rendered", "atorvastatin"], "article_id"=>826264, "categories"=>["Biological Sciences"], "users"=>["Zhu-Hong Li", "Srinivasan Ramakrishnan", "Boris Striepen", "Silvia N. J. Moreno"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003665.s001", "https://dx.doi.org/10.1371/journal.ppat.1003665.s002", "https://dx.doi.org/10.1371/journal.ppat.1003665.s003", "https://dx.doi.org/10.1371/journal.ppat.1003665.s004", "https://dx.doi.org/10.1371/journal.ppat.1003665.s005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Toxoplasma_gondii_Relies_on_Both_Host_and_Parasite_Isoprenoids_and_Can_Be_Rendered_Sensitive_to_Atorvastatin/826264", "title"=>"<i>Toxoplasma gondii</i> Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-17 02:46:25"}

PMC Usage Stats | Further Information

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Relative Metric

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