{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:34:53Z","timestamp":1780526093004,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012907","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000}}],"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NEI","award":["EY018341"],"award-info":[{"award-number":["EY018341"]}]},{"name":"NIH\/NEI","award":["F31EY035156"],"award-info":[{"award-number":["F31EY035156"]}]},{"name":"NIH\/NEI","award":["P30 EY011373"],"award-info":[{"award-number":["P30 EY011373"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The intracellular protozoan <jats:italic>Toxoplasma gondii<\/jats:italic> manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that <jats:italic>T<\/jats:italic>. <jats:italic>gondii<\/jats:italic> activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report <jats:italic>T<\/jats:italic>. <jats:italic>gondii<\/jats:italic> activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. <jats:italic>T<\/jats:italic>. <jats:italic>gondii<\/jats:italic> promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by <jats:italic>T<\/jats:italic>. <jats:italic>gondii<\/jats:italic> that enables its survival and is central to the development of neural toxoplasmosis.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012907","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T18:46:20Z","timestamp":1738003580000},"page":"e1012907","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt"],"prefix":"10.1371","volume":"21","author":[{"given":"Alyssa","family":"Hubal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Vendhoti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles N.","family":"Shaffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Vos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalitza Lopez","family":"Corcino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5602-1439","authenticated-orcid":true,"given":"Carlos S.","family":"Subauste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"issue":"9","key":"ppat.1012907.ref001","first-page":"a006114","article-title":"Subversion of cell signaling by pathogens","volume":"4","author":"NM Alto","year":"2012","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"ppat.1012907.ref002","doi-asserted-by":"crossref","first-page":"624094","DOI":"10.3389\/fcimb.2021.624094","article-title":"Interferons: Tug of War Between Bacteria and Their Host","volume":"11","author":"N Alphonse","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"issue":"1","key":"ppat.1012907.ref003","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/imr.12892","article-title":"Cross talk between intracellular pathogens and cell death","volume":"297","author":"B Demarco","year":"2020","journal-title":"Immunol Rev"},{"key":"ppat.1012907.ref004","doi-asserted-by":"crossref","first-page":"4426","DOI":"10.2741\/3015","article-title":"The diverse functions of Src family kinases in macrophages","volume":"13","author":"CL Abram","year":"2008","journal-title":"Front Biosci"},{"issue":"11","key":"ppat.1012907.ref005","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20201314","article-title":"Lessons from Toxoplasma: Host responses that mediate parasite control and the microbial effectors that subvert them","volume":"218","author":"EM Frickel","year":"2021","journal-title":"J Exp Med"},{"key":"ppat.1012907.ref006","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.3389\/fimmu.2017.01080","article-title":"Host-Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response","volume":"8","author":"TR Brasil","year":"2017","journal-title":"Front Immunol"},{"key":"ppat.1012907.ref007","doi-asserted-by":"crossref","first-page":"673813","DOI":"10.3389\/fcell.2021.673813","article-title":"Recent Advances in the Roles of Autophagy and Autophagy Proteins in Host Cells During Toxoplasma gondii Infection and Potential Therapeutic Implications","volume":"9","author":"CS Subauste","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"3","key":"ppat.1012907.ref008","doi-asserted-by":"crossref","first-page":"e90203","DOI":"10.1371\/journal.pone.0090203","article-title":"Toxoplasmosis\u2014a global threat. 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