T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
基本信息
- 批准号:7893819
- 负责人:
- 金额:$ 19.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-15 至 2012-10-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAffectAntibodiesAntigensApicalAttenuatedBindingBiological AssayBiological ModelsBiologyCarbohydratesCellsChildhoodComplexCryptosporidiosisCryptosporidiumDataDeveloping CountriesDevelopmental Delay DisordersDiarrheaDiseaseDisease OutbreaksEnzymesEpithelial CellsEpitopesEscherichia coliFutureGastrointestinal DiseasesGlycoproteinsGoalsGrowthHumanImmuneImmune responseImmunocompromised HostIn VitroInfectionIntestinesInvadedInvestigationLabelLectinLifeMeasuresMethodsModelingMolecularMonosaccharidesMucinsMusOligosaccharidesOpportunistic InfectionsOrganellesParasitesPatientsPatternPlayPolysaccharidesPopulationPost-Translational Protein ProcessingProcessProteinsProteolytic ProcessingProteomicsReceptor CellRecombinantsRelative (related person)RoleSerumSporozoitesStagingStructureSurfaceSystemT-Lymphocyte EpitopesTechniquesToxoplasma gondiiVaccinesVirulence FactorsWatercell mediated immune responseeffective therapyglycosylationimmune functionimmunogenicimmunogenicitypathogenpressurepublic health relevanceresearch studytherapeutic vaccinevaccine developmentvector vaccinewaterborne
项目摘要
DESCRIPTION (provided by applicant): Cryptosporidium (Cp) is a ubiquitous waterborne pathogen that causes diarrheal disease worldwide. This pathogen causes life-threatening diarrheal disease in immunocompromised hosts, particularly AIDS patients. To date there is no effective treatment or vaccine for Cp. Studies suggest that Cp relies on mucin- like glycoproteins to attach to and invade intestinal epithelial cells. These mucin antigens are also targets of protective cellular immune responses. However, investigating the role of these antigens in host cell invasion and immune recognition is hampered by the difficulty of studying this parasite which cannot be genetically manipulated or propagated in vitro. To address the need for an expression system that mimics post-translational modifications of the native Cp mucins, we expressed Cp glycoproteins in the related apicomplexan Toxoplasma gondii (Tg). Our previous studies have demonstrated that Tg-expressed Cp mucins are glycosylated, proteolytically processed and localized similarly to the native glycoprotein. However, size discrepancies between the native and Tg- expressed antigens suggests that there may be subtle differences in glycosylation and/or proteolytic processing. In this application we propose to compare the post-translational modifications of a native and Tg- expressed Cp mucin antigen, and determine if the Tg-expressed antigen functions similarly to the native antigen in assays of antigen function and immune recognition. For these studies we will use the Cp mucin antigen, CpMuc4. We hypothesize that the Tg expression system can be employed to produce recombinant Cp glycoprotein antigens that will effectively mimic the functions and immunogenicity of the native antigen. The specific aims are: 1. To explore and compare the post-translational modifications of the native and Tg-rCpMuc4. In these studies, we will investigate proteolytic processing and glycan structure of native CpMuc4 and Tg-rCpMuc4. 2. To evaluate the ability of Tg-rCpMuc4 to mimic the function and immunogenicity of the native antigen. These studies will compare the ability of native and Tg rCpMuc4 to bind to intestinal epithelial cells, and inhibit in vitro infection. We will evaluate humoral and cell mediated immune responses in Cp-infected mice and humans using native and Tg-rCpMuc4 as antigens. An exploratory goal of this aim will be to determine if attenuated Tg expressing CpMuc4 can be employed as a vaccine vector delivery system. These studies will provide a thorough analysis of the Tg expression system as a vehicle for producing and studying Cp mucin antigens. Results from these studies will provide preliminary data for future R01 studies on identification of specific epitopes and host cell receptors involved in sporozoite attachment and invasion and the role of mucin glycotopes in host cell recognition and immune responses. PUBLIC HEALTH RELEVANCE: Cryptosporidium (Cp) are ubiquitous water-borne parasites that cause outbreaks of gastrointestinal disease worldwide. Currently there are no vaccines or treatments for this parasite. This study investigates the use of Toxoplasma gondii to study Cp antigens that are candidates for inclusion in a vaccine for cryptosporidiosis.
描述(由申请方提供):隐孢子虫(Cp)是一种普遍存在的水传播病原体,在全球范围内引起炭疽病。这种病原体在免疫功能低下的宿主,特别是艾滋病患者中引起危及生命的淋病。迄今为止,没有有效的治疗方法或疫苗。研究表明,Cp依赖于粘蛋白样糖蛋白附着和侵入肠上皮细胞。这些粘蛋白抗原也是保护性细胞免疫应答的靶标。然而,研究这些抗原在宿主细胞入侵和免疫识别中的作用受到研究这种寄生虫的困难的阻碍,这种寄生虫不能在体外进行遗传操作或繁殖。为了解决需要一个表达系统,模仿天然Cp粘蛋白的翻译后修饰,我们表达Cp糖蛋白在相关的顶复门弓形虫(Tg)。我们以前的研究表明,TG表达的Cp粘蛋白是糖基化,蛋白水解加工和本地化类似的天然糖蛋白。然而,天然抗原和Tg表达抗原之间的大小差异表明糖基化和/或蛋白水解加工可能存在细微差异。在本申请中,我们提出比较天然和Tg表达的Cp粘蛋白抗原的翻译后修饰,并确定Tg表达的抗原在抗原功能和免疫识别测定中是否与天然抗原功能相似。对于这些研究,我们将使用Cp粘蛋白抗原CpMuc 4。我们假设,Tg表达系统可以用来生产重组Cp糖蛋白抗原,将有效地模拟天然抗原的功能和免疫原性。具体目标是:1.探索和比较天然和Tg-rCpMuc 4的翻译后修饰。在这些研究中,我们将研究天然CpMuc 4和Tg-rCpMuc 4的蛋白水解加工和聚糖结构。2.评价Tg-rCpMuc 4模拟天然抗原的功能和免疫原性的能力。这些研究将比较天然和Tg rCpMuc 4结合肠上皮细胞并抑制体外感染的能力。我们将使用天然和Tg-rCpMuc 4作为抗原来评估Cp-infected小鼠和人类的体液和细胞介导的免疫应答。该目的的探索性目标将是确定表达CpMuc 4的减毒Tg是否可以用作疫苗载体递送系统。这些研究将提供一个彻底的分析Tg表达系统作为一种工具,用于生产和研究Cp粘蛋白抗原。从这些研究结果将提供初步数据,为未来的R 01的研究鉴定的具体表位和宿主细胞受体参与子孢子的附着和入侵和粘蛋白糖表位在宿主细胞识别和免疫反应中的作用。公共卫生相关性:隐孢子虫(Cp)是一种普遍存在的水传播寄生虫,可引起全球范围内的胃肠道疾病爆发。目前还没有针对这种寄生虫的疫苗或治疗方法。本研究探讨了使用弓形虫研究Cp抗原,包括在隐孢子虫病疫苗的候选人。
项目成果
期刊论文数量(0)
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ROBERTA M O'CONNOR其他文献
ROBERTA M O'CONNOR的其他文献
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{{ truncateString('ROBERTA M O'CONNOR', 18)}}的其他基金
Antiparasitic metabolites from deep subterranean fungi for the treatment of cryptosporidiosis, an AIDS defining disease
来自深层地下真菌的抗寄生虫代谢物用于治疗隐孢子虫病(一种艾滋病定义的疾病)
- 批准号:
10698574 - 财政年份:2023
- 资助金额:
$ 19.92万 - 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
- 批准号:
10495750 - 财政年份:2020
- 资助金额:
$ 19.92万 - 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
- 批准号:
10402287 - 财政年份:2020
- 资助金额:
$ 19.92万 - 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
- 批准号:
10631912 - 财政年份:2020
- 资助金额:
$ 19.92万 - 项目类别:
Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease
开发一种新的海洋天然产品来治疗隐孢子虫病(一种艾滋病定义的疾病)
- 批准号:
10076207 - 财政年份:2020
- 资助金额:
$ 19.92万 - 项目类别:
Investigation of a shipworm endosymbiont compound with activity against the AIDS-associated pathogens Cryptosporidium and Toxoplasma
对具有抗艾滋病相关病原体隐孢子虫和弓形虫活性的船虫内共生化合物的研究
- 批准号:
9267939 - 财政年份:2017
- 资助金额:
$ 19.92万 - 项目类别:
Investigation of a shipworm endosymbiont compound with activity against the AIDS-associated pathogens Cryptosporidium and Toxoplasma
对具有抗艾滋病相关病原体隐孢子虫和弓形虫活性的船虫内共生化合物的研究
- 批准号:
9431036 - 财政年份:2017
- 资助金额:
$ 19.92万 - 项目类别:
T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
- 批准号:
8111486 - 财政年份:2010
- 资助金额:
$ 19.92万 - 项目类别:
T. gondii as a model for investigation of Cryptosporidium glycoprotein antigens
弓形虫作为研究隐孢子虫糖蛋白抗原的模型
- 批准号:
7756965 - 财政年份:2009
- 资助金额:
$ 19.92万 - 项目类别:
Role of Cryptosporidium Mucins in Host-parasite interactions
隐孢子虫粘蛋白在宿主-寄生虫相互作用中的作用
- 批准号:
7168031 - 财政年份:2006
- 资助金额:
$ 19.92万 - 项目类别:
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