{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:51:09Z","timestamp":1790229069150,"version":"4.1.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2015,6,23]],"date-time":"2015-06-23T00:00:00Z","timestamp":1435017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2015,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Although it is established that oxygen availability regulates cellular metabolism and growth, little is known regarding how intracellular pathogens use host factors to grow at physiological oxygen levels. Therefore, large-scale human small interfering RNA screening was performed to identify host genes important for growth of the intracellular protozoan parasite\n            <jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>\n            at tissue oxygen tensions. Among the genes identified by this screen, we focused on the hexokinase 2 (HK2) gene because its expression is regulated by hypoxia-inducible transcription factor 1 (HIF-1), which is important for\n            <jats:italic>Toxoplasma<\/jats:italic>\n            growth.\n            <jats:italic>Toxoplasma<\/jats:italic>\n            increases host HK2 transcript and protein levels in a HIF-1-dependent manner. In addition, parasite growth at 3% oxygen is restored in HIF-1-deficient cells transfected with HK2 expression plasmids. Both HIF-1 activation and HK2 expression were accompanied by increases in host glycolytic flux, suggesting that enhanced HK2 expression in parasite-infected cells is functionally significant. Parasite dependence on host HK2 and HIF-1 expression is not restricted to transformed cell lines, as both are required for parasite growth in nontransformed C2C12 myoblasts and HK2 is upregulated\n            <jats:italic>in vivo<\/jats:italic>\n            following infection. While HK2 is normally associated with the cytoplasmic face of the outer mitochondrial membrane at physiological O\n            <jats:sub>2<\/jats:sub>\n            levels, HK2 relocalizes to the host cytoplasm following infection, a process that is required for parasite growth at 3% oxygen. Taken together, our findings show that HIF-1-dependent expression and relocalization of HK2 represent a novel mechanism by which\n            <jats:italic>Toxoplasma<\/jats:italic>\n            establishes its replicative niche at tissue oxygen tensions.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Little is known regarding how the host cell contributes to the survival of the intracellular parasite\n            <jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>\n            at oxygen levels that mimic those found in tissues. Our previous work showed that\n            <jats:italic>Toxoplasma<\/jats:italic>\n            activates the expression of an oxygen-regulated transcription factor that is required for growth. Here, we report that\n            <jats:italic>Toxoplasma<\/jats:italic>\n            regulates the abundance and activity of a key host metabolic enzyme, hexokinase 2, by activating HIF-1 and by promoting dissociation of hexokinase 2 from the mitochondrial membrane. Collectively, our data reveal HIF-1\/hexokinase 2 as a novel target for an intracellular pathogen that acts by reprograming the host cell's metabolism to create an environment conducive for parasite replication at physiological oxygen levels.\n          <\/jats:p>","DOI":"10.1128\/mbio.00462-15","type":"journal-article","created":{"date-parts":[[2015,6,24]],"date-time":"2015-06-24T01:05:14Z","timestamp":1435107914000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["siRNA Screening Identifies the Host Hexokinase 2 (HK2) Gene as an Important Hypoxia-Inducible Transcription Factor 1 (HIF-1) Target Gene in Toxoplasma gondii-Infected Cells"],"prefix":"10.1128","volume":"6","author":[{"given":"Matthew T.","family":"Menendez","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"},{"name":"Department of Microbiology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Teygong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Wade","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Florimond","sequence":"additional","affiliation":[{"name":"Department of Microbiology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J.","family":"Blader","sequence":"additional","affiliation":[{"name":"Department of Microbiology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"},{"name":"Department of Ophthalmology, SUNY at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.251470"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066373"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108181200"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101470"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3038"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00420"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(88)90090-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708216200"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803614200"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017674"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(92)90625-7"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2003.12.009"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2010.00992.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100951200"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00628.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064693"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2527"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2012.07.011"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511397200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20060217"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.11.3005"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12342"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/270725a0"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00517.x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2010.11.005"},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","unstructured":"Ardehali H Yano Y Printz RL Koch S Whitesell RR May JM Granner DK. 1996. 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