Trypanosome Transmission Biology in Tsetse

采采蝇中的锥虫传播生物学

• 批准号: 10365155
• 负责人: Serap AKSOY
• 金额: $ 85.12万
• 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/10365155
• 关键词: Address; 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 response; Immunity; Immunologics; Immunology; Infection; Influentials; Insect Vectors; Interruption; Investigation; Knowledge; Laboratories; Mammals; Mediating; Membrane Glycoproteins; Membrane Proteins; Methods; MicroRNAs; Midgut; Modification; Molecular; Nutrient; 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; symbiont; tool; translational applications; 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.

该应用针对的是人类非洲锥虫病 (HAT)，这是亚种最被忽视的疾病之一。 撒哈拉非洲。尽管预计到 2030 年消除冈比亚病，但在冲突频发的地区仍无法控制冈比亚病 HAT 通常发生的偏远地区仍然具有挑战性。罗得西亚病的中断并不是 由于野生动物和家养动物宿主的存在，目前尚未实现这一设想。因为相关采采蝇 传播的寄生虫也会在家畜中引起毁灭性的消耗性疾病，我们的研究也表明 提高非洲大陆的养分供应和农业生产力。虽然已经取得了相当大的进展 尽管最近提出了治愈患者的疗法，但预防疾病的工具箱仍然不足。最近的 哺乳动物咬合部位生物学的发现为新方法的开发开辟了新领域 当唾液中引入的寄生虫很少时，可以防止哺乳动物感染早期的传播。 在这里，我们将发展分子和免疫学对话的基础以及影响因素 最终影响咬伤部位的疾病进展。这些信息将有助于评估项目的可行性 针对采采蝇唾液中传播的后循环寄生虫的传播阻断疫苗（TBV）策略。 目标 1. 了解唾液腺 (SG) 中采采蝇与锥虫对话的机制基础。我们的数据 表明锥虫感染会改变采采蝇 SG 基因表达和唾液成分（唾液成分）。到 为了了解寄生虫与 SG 的分子对话，我们将： 1) 描述正常和正常情况下的 miRNA 群体特征 感染的 SG，2) 验证候选 miRNA 在产品调节中的功能参与 传染性接种物，3) 确定寄生虫感染介导的对 SG 生理和唾液的影响 自然采采蝇种群的组成。 目标 2. 表征咬伤部位的后循环锥虫传播并阐明载体衍生因素 协调这个过程。我们的数据表明，受感染哺乳动物的不同组织具有不同的特征 血流群体形成锥虫。更好地了解介导寄生虫感染的因素 在哺乳动物宿主的动态中，我们将确定：1）宿主-寄生虫期间的时间和空间对话 从咬伤部位传播到血液和周围器官，以及 2) 咬伤处的免疫学对话 与唾液中传播的多种因子（外泌体和唾液传播的共生体）一起。 目标 3. 研究表面蛋白家族 (Fam10) 以阻止哺乳动物叮咬处寄生虫的发育 地点。我们的研究鉴定了 mMC 细胞表面表达的一个蛋白质家族 (Fam10)，并证明 针对一名 Fam10 成员的疫苗接种可减少感染早期的寄生虫血症。评估可行性 对于 TBV 方法，我们将：1) 研究天然锥虫种群中 Fam10 蛋白的多样性，2) 筛选保守的免疫原性肽，3) 测试针对多种肽抗体的疫苗功效 保守的 Fam10 抗原，4) 确定咬伤部位保护性免疫的决定因素。