{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:46:23Z","timestamp":1778647583302,"version":"3.51.4"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS095994"],"award-info":[{"award-number":["NS095994"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS095994-02S1"],"award-info":[{"award-number":["NS095994-02S1"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurologic Disorders and Stroke","doi-asserted-by":"crossref","award":["NIAID AI157247"],"award-info":[{"award-number":["NIAID AI157247"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100019002","name":"BIO5 Institute, University of Arizona","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Toxoplasma gondii<\/jats:italic> is an intracellular parasite that establishes a long-term infection in the brain of many warm-blooded hosts, including humans and rodents. Like all obligate intracellular microbes, <jats:italic>Toxoplasma<\/jats:italic> uses many effector proteins to manipulate the host cell to ensure parasite survival. While some of these effector proteins are universal to all <jats:italic>Toxoplasma<\/jats:italic> strains, some are polymorphic between <jats:italic>Toxoplasma<\/jats:italic> strains. One such polymorphic effector is GRA15. The <jats:italic>gra15<\/jats:italic> allele carried by type II strains activates host NF-\u03baB signaling, leading to the release of cytokines such as IL-12, TNF, and IL-1\u03b2 from immune cells infected with type II parasites. Prior work also suggested that GRA15 promotes early host control of parasites <jats:italic>in vivo<\/jats:italic>, but the effect of GRA15 on parasite persistence in the brain and the peripheral immune response has not been well defined. For this reason, we sought to address this gap by generating a new II\u0394<jats:italic>gra15<\/jats:italic> strain and comparing outcomes at 3 weeks post infection between WT and II\u0394<jats:italic>gra15<\/jats:italic> infected mice. We found that the brain parasite burden and the number of macrophages\/microglia and T cells in the brain did not differ between WT and II\u0394<jats:italic>gra15<\/jats:italic> infected mice. In addition, while II\u0394<jats:italic>gra15<\/jats:italic> infected mice had a lower number and frequency of splenic M1-like macrophages and frequency of PD-1+ CTLA-4+ CD4+ T cells and NK cells compared to WT infected mice, the IFN-\u03b3+ CD4 and CD8 T cell populations were equivalent. In summary, our results suggest that <jats:italic>in vivo<\/jats:italic> GRA15 may have a subtle effect on the peripheral immune response, but this effect is not strong enough to alter brain parasite burden or parenchymal immune cell number at 3 weeks post infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0300764","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T17:23:30Z","timestamp":1711733010000},"page":"e0300764","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Toxoplasma type II effector GRA15 has limited influence in vivo"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9449-4683","authenticated-orcid":true,"given":"Emily 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Required for Efficient Persistence of Bradyzoites","volume":"9","author":"CE Caffaro","year":"2013","journal-title":"PLOS Pathogens"},{"issue":"24","key":"pone.0300764.ref024","doi-asserted-by":"crossref","first-page":"14010","DOI":"10.1074\/jbc.271.24.14010","article-title":"Insertional Tagging, Cloning, and Expression of the Toxoplasma gondii Hypoxanthine-Xanthine-Guanine Phosphoribosyltransferase Gene: USE AS A SELECTABLE MARKER FOR STABLE TRANSFORMATION *","volume":"271","author":"RGK Donald","year":"1996","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"pone.0300764.ref025","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nmeth.1438","article-title":"Toxoplasma secreting Cre recombinase for analysis of host-parasite interactions","volume":"7","author":"AA Koshy","year":"2010","journal-title":"Nat 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Immunology"},{"issue":"10","key":"pone.0300764.ref029","doi-asserted-by":"crossref","first-page":"e1007856","DOI":"10.1371\/journal.ppat.1007856","article-title":"The ROP16III-dependent early immune response determines the subacute CNS immune response and type III Toxoplasma gondii survival","volume":"15","author":"S Tuladhar","year":"2019","journal-title":"PLOS Pathogens"},{"issue":"5","key":"pone.0300764.ref030","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1128\/IAI.01314-09","article-title":"CCR7-Dependent Immunity during Acute Toxoplasma gondii Infection","volume":"78","author":"S Noor","year":"2010","journal-title":"Infect Immun"},{"issue":"2","key":"pone.0300764.ref031","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1128\/MCB.18.2.807","article-title":"Isolation of developmentally regulated genes from Toxoplasma gondii by a gene trap with the positive and negative selectable marker hypoxanthine-xanthine-guanine phosphoribosyltransferase","volume":"18","author":"LJ Knoll","year":"1998","journal-title":"Mol Cell Biol"},{"issue":"4","key":"pone.0300764.ref032","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.cell.2013.04.007","article-title":"Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection","volume":"153","author":"NJ Tubo","year":"2013","journal-title":"Cell"},{"issue":"1","key":"pone.0300764.ref033","doi-asserted-by":"crossref","first-page":"13991","DOI":"10.1038\/s41598-019-50614-1","article-title":"IL-12 signaling drives the differentiation and function of a TH1-derived TFH1-like cell population","volume":"9","author":"MD Powell","year":"2019","journal-title":"Sci Rep"},{"issue":"22","key":"pone.0300764.ref034","doi-asserted-by":"crossref","first-page":"9196","DOI":"10.1073\/pnas.1015298108","article-title":"Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 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