{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:12:48Z","timestamp":1773425568260,"version":"3.50.1"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82372283"],"award-info":[{"award-number":["No. 82372283"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018592","name":"\u00e2\u20ac\u0153333 Project\u00e2\u20ac of Jiangsu Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018592","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013254","name":"National College Students Innovation and Entrepreneurship Training Program","doi-asserted-by":"publisher","award":["No. 202210313056Z"],"award-info":[{"award-number":["No. 202210313056Z"]}],"id":[{"id":"10.13039\/501100013254","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013254","name":"National College Students Innovation and Entrepreneurship Training Program","doi-asserted-by":"publisher","award":["No. 202410313014Z"],"award-info":[{"award-number":["No. 202410313014Z"]}],"id":[{"id":"10.13039\/501100013254","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012217","name":"Xuzhou Medical University","doi-asserted-by":"publisher","award":["No. QL-YB022"],"award-info":[{"award-number":["No. QL-YB022"]}],"id":[{"id":"10.13039\/501100012217","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Chronic infection of\n                      <jats:italic>Toxoplasma gondii (T. gondii)<\/jats:italic>\n                      induces the anxiety-like behavior in hosts, which is closely linked to neuroinflammatory processes. Cis-aconite decarboxylase 1 (Acod1) is an enzyme that is responsible for itaconate production in Krebs Cycle. Emerging evidence highlights the Acod1\/itaconate axis as a key regulatory node in macrophage immune-metabolic reprogramming. However, its role in infection-induced neurobehavioral alterations remains unclear. Here, we investigated the role of Acod1\/itaconate axis in the anxiety induced by\n                      <jats:italic>T. gondii<\/jats:italic>\n                      chronic infection in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To assess anxiety-like behaviors, we performed open field test and elevated plus maze test. Transcriptomic alterations and neuroinflammatory responses in the mouse amygdala were profiled\n                      <jats:italic>via<\/jats:italic>\n                      RNA sequencing, immunofluorescence staining, quantitative PCR (qPCR), and western blot. The functional role of the Acod1\/itaconate axis was further investigated using\n                      <jats:italic>Acod1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>-\/-<\/jats:italic>\n                      <\/jats:sup>\n                      mice. Additionally, the therapeutic potential of dimethyl itaconate (DI), a cell-permeable itaconate derivative, was evaluated in chronically\n                      <jats:italic>T. gondii<\/jats:italic>\n                      -infected mice. The levels of indoleamine 2,3-dioxygenase (IDO), and serotonin (5-hydroxytryptamine, 5-HT) in serum were measured by enzyme-linked immunosorbent assay. Finally, DI\u2019s anti-inflammatory mechanism was identified in the microglial cell line BV-2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Chronic\n                      <jats:italic>T. gondii<\/jats:italic>\n                      infection induced anxiety-like behaviors in mice and triggered the activation of Acod1\/itaconate axis in the amygdala. Transcriptomic and histological analyses revealed upregulation of neuroinflammation-related genes, along with microglia activation. Genetic knockout of\n                      <jats:italic>Acod1<\/jats:italic>\n                      induced the anxiety-like phenotypes, which were rescued by DI administration. Notably, DI treatment conferred both prophylactic and therapeutic benefits, effectively mitigating anxiety induced by infection. Mechanistically, DI suppressed\n                      <jats:italic>T. gondii<\/jats:italic>\n                      -induced M1 polarization in microglia to mitigate neuroinflammation via activating Nrf2 signaling. These events further reduced indoleamine IDO expression, leading to increased 5-HT levels and subsequent amelioration of anxiety-like behavior.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that the Acod1\/itaconate axis plays an important role in regulating anxiety-like behavior by modulating neuroinflammation during chronic\n                      <jats:italic>T. gondii<\/jats:italic>\n                      infection. These results reveal a promising immune-metabolic drug target for treating\n                      <jats:italic>T. gondii<\/jats:italic>\n                      -associated neuropsychiatric conditions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0014077","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:42:24Z","timestamp":1773423744000},"page":"e0014077","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acod1\/itaconate axis controls anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Ziyi","family":"Yan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingting","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiling","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinde","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2641-1759","authenticated-orcid":true,"given":"Wei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fenfen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"pntd.0014077.ref001","unstructured":"Organization WH. 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