Trypanosome Transmission Biology in Tsetse

采采蝇中的锥虫传播生物学

• 批准号: 10542426
• 负责人: Serap AKSOY
• 金额: $ 81.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-17 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542426
• 关键词: Africa; Africa South of the Sahara; African; Agriculture; Animals; Antigenic Variation; Antigens; Area; Biology; Bite; Blood; Blood Circulation; Bypass; Cells; Conflict (Psychology); Data; Development; Disease; Disease Progression; Domestic Animals; Environment; Epitopes; Event; Family; Foundations; Gene Expression; Human; Immune; Immune Evasion; Immune response; Immunity; Immunologics; Immunology; Infection; Influentials; Insecta; Interruption; Investigation; Knowledge; Laboratories; Mammals; Mediating; Membrane Glycoproteins; Membrane Proteins; Methods; MicroRNAs; Midgut; Modification; Molecular; Nutrient availability; Organ; Parasitemia; Parasites; Parasitic infection; Parasitology; Patients; Peptide antibodies; Peptides; Peripheral; Physiology; Population; Process; Production; Productivity; Protein Family; Proteins; Public Health; Regulation; Saliva; Salivary Glands; Shapes; Site; Surface; Techniques; Testing; Therapeutic; Thick; Time; Tissues; Transfer Factor; Trypanosoma; Trypanosoma brucei brucei; Tsetse Flies; Uganda; Vaccinated; Vaccination; Vaccines; Variant; Wasting Syndrome; Wild Animals; World Health Organization; Zoonoses; disorder control; disorder prevention; exosome; experimental study; fly; frontier; immunogenic; improved; member; mouse model; neglect; novel; prevent; programs; protein expression; saliva composition; single-cell RNA sequencing; surface coating; symbiont; tool; translational applications; transmission blocking; transmission process; transmission-blocking vaccine; vaccine efficacy; vaccine evaluation; vaccine strategy; vector

This application is on Human African Trypanosomiases (HAT), one of the most neglected diseases of sub- Saharan Africa. Despite the anticipated elimination of the gambiense disease by 2030, control in conflict-ridden and remote areas where HAT typically occurs remains challenging. Interruption of the rhodesiense disease is not yet envisioned at this time due to the presence of wild and domestic animal reservoirs. Because related tsetse- transmitted parasites also cause devastating wasting diseases in domestic animals, our studies stand to also improve nutrient availability and agricultural productivity on the continent. While considerable progress has been recently made on therapeutics to cure patients, the tool box for disease prevention remains inadequate. Recent discoveries on the mammalian bite site biology opened up a new frontier for the development of novel methods to prevent transmission early in the infection in the mammal when very few parasites are introduced in saliva. Here, we will develop the foundation on the molecular and immunological dialogues and the influential factors that ultimately shape disease progression at the bite site. This information will help evaluate the feasibility of a transmission blocking vaccine (TBV) strategy that target metacyclic parasites transmitted in tsetse saliva. Aim 1. Understand the mechanistic basis of the tsetse-trypanosome dialogue in salivary glands (SG). Our data indicate that trypanosome infections modify tsetse SG gene expression and saliva components (sialome). To understand the parasite-SG molecular dialogue, we will: 1) characterize the miRNA populations in normal and infected SGs, 2) validate the functional involvement of candidate miRNAs in the regulation of products in the infectious inoculum, and 3) determine parasite infection mediated effects on SG physiology and saliva composition in natural tsetse populations. Aim 2. Characterize metacyclic trypanosome dissemination at the bite-site and elucidate vector-derived factors that orchestrate this process. Our data indicate that the different tissues of infected mammals harbor distinct populations of bloodstream form trypanosomes. To better understand the factors that mediate parasite infection dynamics in the mammalian host, we will determine: 1) the temporal and spatial host-parasite dialogue during dissemination from the bite site to blood and peripheral organs, and 2) the immunological dialogue at the bite site together with multiple factors transmitted in saliva (exosomes and saliva-borne symbionts). Aim 3. Investigate a family of surface proteins (Fam10) to block parasite development at the mammalian bite site. Our studies identified a family of proteins (Fam10) expressed on the surface of mMC cells and demonstrated that vaccination against one Fam10 member reduces parasitemia early in the infection. To evaluate the feasibility of TBV methods, we will: 1) investigate the diversity of Fam10 proteins in natural trypanosome populations, 2) screen for conserved immunogenic peptides, 3) test vaccine efficacy of peptide antibodies that target multiple conserved Fam10 antigens, and 4) identify the determinants of protective immunity at the bite site.

该应用是关于人类非洲锥虫（HAT）的应用，这是该亚地区最被忽视的疾病之一 撒哈拉非洲。尽管预计到2030年消除了甘比氏病，但控制冲突困扰 帽子通常发生的偏远地区仍然具有挑战性。中断罗登山疾病不是 由于存在野生动物和家畜的水库，但此时仍设想。因为相关的采摘 传播的寄生虫还会引起家畜中的毁灭性浪费疾病，我们的研究也将 提高大陆上的养分利用率和农业生产率。虽然取得了很大的进步 最近对治疗患者的治疗方法进行了预防疾病的工具盒，仍然不足。最近的 哺乳动物叮咬站点生物学上的发现为开发新方法开发了新的边界 为了防止在唾液中引入很少的寄生虫时，哺乳动物的感染早期传播。 在这里，我们将建立关于分子和免疫对话的基础，以及影响因素 最终在咬伤部位塑造疾病进展。此信息将有助于评估 传输阻断疫苗（TBV）策略，其靶向采用唾液中传播的元环寄生虫。 目的1。了解唾液腺（SG）中采用ttse-trypanosom对话的机械基础。我们的数据 表明锥虫感染改变了TSETSE SG基因表达和唾液成分（Sialome）。到 了解寄生虫-SG分子对话，我们将：1）在正常和 感染的SGS，2）验证候选miRNA在调节产品中的功能参与 感染性接种物和3）确定寄生虫感染介导的对SG生理学和唾液的影响 自然采集种群中的组成。 AIM 2。在咬合位置表征元环锥体传播并阐明载体衍生的因子 该过程策划了这一过程。我们的数据表明，感染的哺乳动物的不同组织具有独特的 血液的种群形成锥虫。更好地了解介导寄生虫感染的因素 哺乳动物宿主的动态，我们将确定：1）时间和空间宿主 - 寄生虫对话 从咬伤部位传播到血液和外围器官，以及2）咬合的免疫对话 位置以及在唾液中传播的多种因素（外泌体和唾液传播的共生体）。 目标3。研究表面蛋白（FAM10）的家族以阻断哺乳动物咬合的寄生虫发育 地点。我们的研究确定了在MMC细胞表面表达的蛋白质家族（FAM10），并证明了 对一个FAM10成员的疫苗接种可在感染初期降低寄生虫病。评估可行性 在TBV方法中，我们将：1）研究自然锥虫种群中FAM10蛋白的多样性，2） 筛选保守的免疫原性肽，3）测试靶向多重肽抗体的疫苗疗效 保守的FAM10抗原，4）确定咬伤部位保护性免疫的决定因素。