Trichomonas vaginalis exosomes: Mediators of host:pathogen interactions

阴道毛滴虫外泌体：宿主：病原体相互作用的介质

• 批准号: 8850804
• 负责人: Patricia Jean Johnson
• 金额: $ 59.36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850804
• 关键词: Address; Adherence; Affect; Antigen Presentation; Area; Binding; Biochemical; Candidate Disease Gene; Case Study; Cell Communication; Cell physiology; Cells; Cervicitis; Cytolysis; Development; Disease; Drug resistance; Epithelial Cells; Gene Expression; Genitourinary system; Goals; HIV; Health; Human; Incidence; Infection; Knowledge; Lead; Learning; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Mammalian Cell; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Neoplasm Metastasis; Organism; Outcome; Parasites; Pathogenesis; Pathway interactions; Pelvic Inflammatory Disease; Pharmaceutical Preparations; Play; Pregnancy Outcome; Prevalence; Probability; Process; Proteins; Proteome; Proteomics; Regulation; Reporting; Research; Risk; Role; Severities; Sexually Transmitted Diseases; Small RNA; Surface; Technology; Therapeutic; Trichomonas Infections; Trichomonas vaginalis; Urethritis; Vaccine Design; Vagina; Vaginitis; Vesicle; crosslinking and immunoprecipitation sequencing; design; extracellular; human PHEMX protein; immunoregulation; interest; mRNA Expression; novel; pathogen; protein expression; response; transcriptome sequencing; transmission process; vaccine candidate

DESCRIPTION (provided by applicant): The unicellular parasite Trichomonas vaginalis is responsible for the most prevalent non-viral sexually transmitted infection worldwide, with approximately 170 million cases of trichomoniasis reported annually. In the US alone, the annual incidence is estimated at 3-5 million cases. In addition to infecting the human urogenital tract, trichomoniasis increases the risk of adverse pregnancy outcomes, HIV transmission and the incidence and severity of cervical and prostate cancers. It's prevalence and the recent increase in the number of drug resistant T. vaginalis strains underscore the need to develop new chemotherapeutic and vaccine design strategies. A much better understanding of processes involved in infectivity and pathogenesis, such as those proposed here, will be imperative to achieve these goals. We have discovered that T. vaginalis secretes small, membrane-bound vesicles, called exosomes, which are capable of fusing with and delivering proteins into the host cell. Parasite exosomes can also modulate host cell responses. The exosome-mediated host:pathogen interactions that we observed is an entirely new area of research that promises to uncover interesting, novel mechanisms. Our objectives are to further characterize exosome:host cell interactions and investigate the effect of exosomes on global host cell response. To this end, our studies will focus on characterizing exosomal fusion with host cells and exosome-mediated modulation of host cell gene and protein expression. The specfic aims of the proposal are: Aim 1: Determine whether the conserved exosomal membrane protein, tetraspanin 1, plays a vital role in exosome fusion with host cells and if this is mediate by selection of specific exosomal membrane-associated proteins. Aim 2: Determine whether exosomes from highly adherent and cytolytic T. vaginalis strains increase the ability of weakly adherent/cytolytic strains to adhere to and/or lyse vaginal epithelial cells. The exosomal proteomes of these strains will also be compared to identify candidate proteins involved in adherence and cytolysis. Aim 3: [Examine how] T. vaginalis exosomes modulate host cell responses by altering gene and protein expression in target human vaginal epithelial cells. These studies will greatly enhance our understanding of processes underlying the infectivity and pathogenesis of a prevalent human pathogen and have a high probability of revealing novel mechanisms used by the parasite to mediate host:pathogen interactions. As exosomes are also produced by mammalian cells and are known to play critical roles in both normal and pathological cellular functions, what we learn from the proposed studies is likely to also contribute to a better understanding of the role of exosomes in development, antigen presentation, immune modulation and cancer metastasis.

描述（由申请人提供）：单细胞寄生虫阴道毛滴虫是全世界最流行的非病毒性传播感染的罪魁祸首，每年报告约 1.7 亿例滴虫病病例。仅在美国，每年的发病率估计就有 3-500 万例。除了感染人类泌尿生殖道外，滴虫病还会增加不良妊娠结局、艾滋病毒传播以及宫颈癌和前列腺癌的发病率和严重程度的风险。它的流行和最近耐药性阴道毛滴虫菌株数量的增加强调了开发新的化疗和疫苗设计策略的必要性。为了实现这些目标，必须更好地了解感染性和发病机制所涉及的过程（例如本文提出的那些过程）。我们发现阴道毛滴虫分泌小的膜结合囊泡，称为外泌体，它能够与宿主细胞融合并将蛋白质递送到宿主细胞中。寄生虫外泌体还可以调节宿主细胞反应。我们观察到的外泌体介导的宿主：病原体相互作用是一个全新的研究领域，有望揭示有趣的新颖机制。我们的目标是进一步表征外泌体：宿主细胞相互作用，并研究外泌体对整体宿主细胞反应的影响。为此，我们的研究将集中于表征外泌体与宿主细胞的融合以及外泌体介导的宿主细胞基因和蛋白质表达的调节。该提案的具体目标是： 目标 1：确定保守的外泌体膜蛋白四跨膜蛋白 1 是否在外泌体与宿主细胞融合中发挥至关重要的作用，以及这是否是通过选择特定的外泌体膜相关蛋白来介导的。目标 2：确定来自高度粘附和溶细胞性阴道毛滴虫菌株的外泌体是否会增加弱粘附/溶细胞菌株粘附和/或裂解阴道上皮细胞的能力。还将比较这些菌株的外泌体蛋白质组，以确定参与粘附和细胞溶解的候选蛋白质。目标 3：[研究]阴道毛滴虫外泌体如何通过改变靶人阴道上皮细胞中的基因和蛋白质表达来调节宿主细胞反应。这些研究将极大地增强我们对人类流行病原体的感染性和发病机制的理解，并且很有可能揭示寄生虫介导宿主与病原体相互作用的新机制。由于外泌体也是由哺乳动物细胞产生的，并且已知在正常和病理细胞功能中发挥着关键作用，因此我们从拟议的研究中学到的知识也可能有助于更好地了解外泌体在发育、抗原呈递、免疫调节和癌症转移中的作用。