{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:36:03Z","timestamp":1789058163290,"version":"build-2803163510"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"the National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2018R1A6A1A03025124"],"award-info":[{"award-number":["2018R1A6A1A03025124"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["HV20C0085"],"award-info":[{"award-number":["HV20C0085"]}]},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["HV20C0142"],"award-info":[{"award-number":["HV20C0142"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Toxoplasma gondii<\/jats:italic>host cellular invasion factors such as the rhoptry proteins, micronemal antigens, or other subcellular compartment proteins have shown limited vaccine efficacies.<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>cyst wall protein (CST1) as a cyst persistence factor is critical for cyst wall integrity and bradyzoite persistence. Here, we generated influenza virus-like particles (VLPs) expressing the<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>CST1 and evaluated the mucosal as well as systemic immunities induced by VLPs. Intranasal immunization with the VLPs induced parasite-specific IgG and IgA antibody responses in sera and intestines. VLP immunization showed higher levels of germinal center B cell response and antibody-secreting cell (ASC) response upon challenge infection, indicating memory B cell response was induced. VLP-immunized mice showed a significant reduction of cyst counts and lower levels of pro-inflammatory cytokines (IFN-\u03b3, IL-6) production in the brain upon<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>ME49 challenge infection compared to unimmunized control. Thus, VLP immunization protected mice from the lethal dose challenge infection with<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>ME49 and did not incur bodyweight loss. These results indicated that<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>CST1 containing VLPs can induce mucosal and systemic immunity and also suggest its developmental potential as an effective vaccine candidate against<jats:italic>T<\/jats:italic>.<jats:italic>gondii<\/jats:italic>infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0283928","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T17:38:31Z","timestamp":1682617111000},"page":"e0283928","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Protective mucosal and systemic immunity induced by virus-like particles expressing Toxoplasma gondii cyst wall protein"],"prefix":"10.1371","volume":"18","author":[{"given":"Gi-Deok","family":"Eom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki-Back","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-Ji","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Ju","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keon-Woong","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Hwa","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3407-7220","authenticated-orcid":true,"given":"Md Atique","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Kyung","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0419-9339","authenticated-orcid":true,"given":"Fu-Shi","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"issue":"2","key":"pone.0283928.ref001","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1128\/IAI.02536-14","article-title":"CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection","volume":"83","author":"DA Mahamed","year":"2015","journal-title":"Infect Immun"},{"issue":"7","key":"pone.0283928.ref002","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.pt.2017.04.001","article-title":"Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle","volume":"33","author":"EA Wohlfert","year":"2017","journal-title":"Trends Parasitol"},{"issue":"1","key":"pone.0283928.ref003","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s12974-018-1242-1","article-title":"Chronic Toxoplasma infection is associated with distinct alterations in the synaptic protein composition","volume":"15","author":"D Lang","year":"2018","journal-title":"J Neuroinflammation"},{"issue":"4","key":"pone.0283928.ref004","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s11011-016-9822-1","article-title":"The known and missing links between Toxoplasma gondii and schizophrenia","volume":"31","author":"HM Elsheikha","year":"2016","journal-title":"Metab Brain Dis"},{"key":"pone.0283928.ref005","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.3389\/fmicb.2018.02587","article-title":"Drug Resistance in Toxoplasma gondii","volume":"9","author":"M Montazeri","year":"2018","journal-title":"Front Microbiol"},{"issue":"10","key":"pone.0283928.ref006","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.pt.2004.07.009","article-title":"Veterinary parasitic vaccines: pitfalls and future directions","volume":"20","author":"J Vercruysse","year":"2004","journal-title":"Trends Parasitol"},{"key":"pone.0283928.ref007","doi-asserted-by":"crossref","first-page":"105696","DOI":"10.1016\/j.mimet.2019.105696","article-title":"A systematic review on the role of GRA proteins of Toxoplasma gondii in host immunization","volume":"165","author":"F Rezaei","year":"2019","journal-title":"J Microbiol Methods"},{"issue":"3","key":"pone.0283928.ref008","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1128\/CVI.00419-06","article-title":"Use of MAG1 recombinant antigen for diagnosis of Toxoplasma gondii infection in humans","volume":"14","author":"L Holec","year":"2007","journal-title":"Clin Vaccine Immunol"},{"issue":"1","key":"pone.0283928.ref009","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1186\/s12879-021-06873-3","article-title":"Comparison of real-time PCR and nested PCR for toxoplasmosis diagnosis in toxoplasmic retinochoroiditis patients","volume":"21","author":"K Khanaliha","year":"2021","journal-title":"BMC Infect Dis"},{"issue":"1","key":"pone.0283928.ref010","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1128\/IAI.69.1.501-507.2001","article-title":"Initial characterization of CST1, a Toxoplasma gondii cyst wall glycoprotein","volume":"69","author":"YW Zhang","year":"2001","journal-title":"Infect Immun"},{"issue":"12","key":"pone.0283928.ref011","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003823","article-title":"The Toxoplasma gondii cyst wall protein CST1 is critical for cyst wall integrity and promotes bradyzoite persistence","volume":"9","author":"T Tomita","year":"2013","journal-title":"PLoS Pathog"},{"issue":"1","key":"pone.0283928.ref012","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02048-16","article-title":"Making Home Sweet and Sturdy: Toxoplasma gondii ppGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity","volume":"8","author":"T Tomita","year":"2017","journal-title":"mBio"},{"issue":"2","key":"pone.0283928.ref013","doi-asserted-by":"crossref","DOI":"10.1128\/mSphere.00031-20","article-title":"Succinylated Wheat Germ Agglutinin Colocalizes with the Toxoplasma gondii Cyst Wall Glycoprotein CST1","volume":"5","author":"RB Guevara","year":"2020","journal-title":"mSphere"},{"issue":"9\u201310","key":"pone.0283928.ref014","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.micinf.2017.12.003","article-title":"Observations on bradyzoite biology","volume":"20","author":"V Tu","year":"2018","journal-title":"Microbes Infect"},{"key":"pone.0283928.ref015","doi-asserted-by":"crossref","first-page":"104643","DOI":"10.1016\/j.micpath.2020.104643","article-title":"Toxoplasma gondii induces robust humoral immune response against cyst wall antigens in chronically infected animals and humans","volume":"152","author":"AS Deshmukh","year":"2021","journal-title":"Microb Pathog"},{"issue":"2","key":"pone.0283928.ref016","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1586\/14760584.8.2.215","article-title":"Vaccination concepts against Toxoplasma gondii","volume":"8","author":"JL Garcia","year":"2009","journal-title":"Expert Rev Vaccines"},{"issue":"9","key":"pone.0283928.ref017","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.4161\/hv.21006","article-title":"Vaccines against Toxoplasma gondii: status, challenges and future directions","volume":"8","author":"Q Liu","year":"2012","journal-title":"Hum Vaccin Immunother"},{"key":"pone.0283928.ref018","doi-asserted-by":"crossref","first-page":"630682","DOI":"10.3389\/fmicb.2021.630682","article-title":"Immunization With a DNA Vaccine Encoding the Toxoplasma gondii\u2019 s GRA39 Prolongs Survival and Reduce Brain Cyst Formation in a Murine Model","volume":"12","author":"Y Zhu","year":"2021","journal-title":"Front Microbiol"},{"issue":"11","key":"pone.0283928.ref019","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0143087","article-title":"Vaccination with Recombinant Microneme Proteins Confers Protection against Experimental Toxoplasmosis in Mice","volume":"10","author":"CF Pinzan","year":"2015","journal-title":"PLoS One"},{"issue":"38","key":"pone.0283928.ref020","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1016\/j.vaccine.2018.08.016","article-title":"Virus-like particle vaccines expressing Toxoplasma gondii rhoptry protein 18 and microneme protein 8 provide enhanced protection","volume":"36","author":"SH Lee","year":"2018","journal-title":"Vaccine"},{"issue":"14","key":"pone.0283928.ref021","doi-asserted-by":"crossref","first-page":"3899","DOI":"10.1093\/emboj\/17.14.3899","article-title":"A matrix-less measles virus is infectious and elicits extensive cell fusion: consequences for propagation in the brain","volume":"17","author":"T Cathomen","year":"1998","journal-title":"Embo j"},{"issue":"1","key":"pone.0283928.ref022","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1128\/JVI.73.1.242-250.1999","article-title":"Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G","volume":"73","author":"T Mebatsion","year":"1999","journal-title":"J Virol"},{"issue":"24","key":"pone.0283928.ref023","doi-asserted-by":"crossref","first-page":"11538","DOI":"10.1128\/JVI.74.24.11538-11547.2000","article-title":"Influenza virus matrix protein is the major driving force in virus budding","volume":"74","author":"P G\u00f3mez-Puertas","year":"2000","journal-title":"J Virol"},{"issue":"1","key":"pone.0283928.ref024","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.vaccine.2012.10.083","article-title":"Virus-like particles as a highly efficient vaccine platform: diversity of targets and production systems and advances in clinical development","volume":"31","author":"N Kushnir","year":"2012","journal-title":"Vaccine"},{"issue":"1","key":"pone.0283928.ref025","doi-asserted-by":"crossref","first-page":"e12799","DOI":"10.1111\/pim.12799","article-title":"Protective immunity induced by CpG ODN-adjuvanted virus-like particles containing Toxoplasma gondii proteins","volume":"43","author":"HJ Kang","year":"2021","journal-title":"Parasite Immunol"},{"issue":"Web Server issue","key":"pone.0283928.ref026","article-title":"Advantages of combined transmembrane topology and signal peptide prediction\u2014the Phobius web server","volume":"35","author":"L K\u00e4ll","year":"2007","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0283928.ref027","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1128\/JVI.02052-06","article-title":"Virus-like particle vaccine induces protective immunity against homologous and heterologous strains of influenza virus","volume":"81","author":"FS Quan","year":"2007","journal-title":"J Virol"},{"key":"pone.0283928.ref028","first-page":"3073","article-title":"Protective Immunity Induced by Incorporating Multiple Antigenic Proteins of Toxoplasma gondii Into Influenza Virus-Like Particles","volume":"9","author":"SH Lee","year":"2018","journal-title":"Front Immunol"},{"issue":"4","key":"pone.0283928.ref029","article-title":"Protection induced by virus-like particles containing Toxoplasma gondii microneme protein 8 against highly virulent RH strain of Toxoplasma gondii infection","volume":"12","author":"SH Lee","year":"2017","journal-title":"PLoS One"},{"issue":"9","key":"pone.0283928.ref030","doi-asserted-by":"crossref","first-page":"4489","DOI":"10.1128\/JVI.02035-08","article-title":"Kinetics of immune responses to influenza virus-like particles and dose-dependence of protection with a single vaccination","volume":"83","author":"FS Quan","year":"2009","journal-title":"J Virol"},{"issue":"2","key":"pone.0283928.ref031","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3347\/kjp.2019.57.2.93","article-title":"Previous Infection with Plasmodium berghei Confers Resistance to Toxoplasma gondii Infection in Mice","volume":"57","author":"DH Lee","year":"2019","journal-title":"Korean J Parasitol"},{"issue":"10","key":"pone.0283928.ref032","article-title":"Evaluation of CpG-ODN-Adjuvanted Toxoplasma Gondii Virus-Like Particle Vaccine upon One, Two, and Three Immunizations","volume":"12","author":"HJ Kang","year":"2020","journal-title":"Pharmaceutics"},{"issue":"16","key":"pone.0283928.ref033","doi-asserted-by":"crossref","first-page":"9477","DOI":"10.1073\/pnas.95.16.9477","article-title":"T cell-independent type I antibody response against B cell epitopes expressed repetitively on recombinant virus particles","volume":"95","author":"T Fehr","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5138","key":"pone.0283928.ref034","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1126\/science.8248784","article-title":"The influence of antigen organization on B cell responsiveness","volume":"262","author":"MF Bachmann","year":"1993","journal-title":"Science"},{"issue":"1","key":"pone.0283928.ref035","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4049\/jimmunol.0901540","article-title":"Cutting edge: limited specialization of dendritic cell subsets for MHC class II-associated presentation of viral particles","volume":"184","author":"SA Keller","year":"2010","journal-title":"J Immunol"},{"issue":"1","key":"pone.0283928.ref036","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12951-021-00806-7","article-title":"Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers","volume":"19","author":"S Nooraei","year":"2021","journal-title":"J Nanobiotechnology"},{"issue":"3\u20134","key":"pone.0283928.ref037","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ijpara.2017.08.016","article-title":"Toxoplasma gondii-positive human sera recognise intracellular tachyzoites and bradyzoites with diverse patterns of immunoreactivity","volume":"48","author":"MS Roiko","year":"2018","journal-title":"Int J Parasitol"},{"key":"pone.0283928.ref038","doi-asserted-by":"crossref","first-page":"102402","DOI":"10.1016\/j.parint.2021.102402","article-title":"Seroprevalence and risk factors of Toxoplasma gondii infection among veterinary personnel and abattoir workers in Central India","volume":"84","author":"AS Deshmukh","year":"2021","journal-title":"Parasitol Int"},{"key":"pone.0283928.ref039","doi-asserted-by":"crossref","first-page":"102514","DOI":"10.1016\/j.parint.2021.102514","article-title":"Seroprevalence and associated risk factors of Toxoplasma gondii and Neospora caninum infections in cattle in Central India","volume":"87","author":"BK Hebbar","year":"2022","journal-title":"Parasitol Int"},{"issue":"4 Suppl","key":"pone.0283928.ref040","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1038\/nm1213","article-title":"Mucosal immunity and vaccines","volume":"11","author":"J Holmgren","year":"2005","journal-title":"Nat Med"},{"key":"pone.0283928.ref041","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.jconrel.2014.05.060","article-title":"Buccal and sublingual vaccine delivery","volume":"190","author":"H Kraan","year":"2014","journal-title":"J Control Release"},{"key":"pone.0283928.ref042","doi-asserted-by":"crossref","first-page":"735191","DOI":"10.3389\/fcimb.2021.735191","article-title":"Mucosal Administration of Recombinant Baculovirus Displaying Toxoplasma gondii ROP4 Confers Protection Against T. gondii Challenge Infection in Mice","volume":"11","author":"KW Yoon","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"issue":"3","key":"pone.0283928.ref043","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1128\/IAI.68.3.1026-1033.2000","article-title":"B cells are essential for vaccination-induced resistance to virulent Toxoplasma gondii","volume":"68","author":"PC Sayles","year":"2000","journal-title":"Infect Immun"},{"issue":"5","key":"pone.0283928.ref044","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.4049\/jimmunol.164.5.2629","article-title":"Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-gamma, TNF-alpha, and inducible nitric oxide synthase","volume":"164","author":"H Kang","year":"2000","journal-title":"J Immunol"},{"issue":"8","key":"pone.0283928.ref045","article-title":"Virus-like particles containing multiple antigenic proteins of Toxoplasma gondii induce memory T cell and B cell responses","volume":"14","author":"SH Lee","year":"2019","journal-title":"PLoS One"},{"issue":"6","key":"pone.0283928.ref046","doi-asserted-by":"crossref","first-page":"e12716","DOI":"10.1111\/pim.12716","article-title":"Toxoplasma gondii virus-like particle vaccination alleviates inflammatory response in the brain upon T gondii infection","volume":"42","author":"HJ Kang","year":"2020","journal-title":"Parasite Immunol"},{"issue":"1","key":"pone.0283928.ref047","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1128\/iai.51.1.147-156.1986","article-title":"In vitro cultivation of Toxoplasma gondii cysts in astrocytes in the presence of gamma interferon","volume":"51","author":"TC Jones","year":"1986","journal-title":"Infect Immun"},{"issue":"3","key":"pone.0283928.ref048","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.chom.2011.07.009","article-title":"A critical role for SOCS3 in innate resistance to Toxoplasma gondii","volume":"10","author":"RJ Whitmarsh","year":"2011","journal-title":"Cell Host Microbe"},{"key":"pone.0283928.ref049","doi-asserted-by":"crossref","first-page":"106514","DOI":"10.1016\/j.actatropica.2022.106514","article-title":"A recombinant protein vaccine encoding Toxoplasma gondii Cyst wall 2 (dense granule protein 47) provides partial protection against acute and chronic T. gondii infection in BALB\/c mice","volume":"232","author":"X Tian","year":"2022","journal-title":"Acta Trop"},{"issue":"2","key":"pone.0283928.ref050","article-title":"Enrichment and Proteomic Characterization of the Cyst Wall from In Vitro Toxoplasma gondii Cysts","volume":"10","author":"V Tu","year":"2019","journal-title":"mBio"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283928","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T16:33:18Z","timestamp":1702312398000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283928"}},"subtitle":[],"editor":[{"given":"Paulo Lee","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,27]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0283928","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,27]]}}}