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.

这项应用是针对人类非洲锥虫病(HAT)，这是亚细菌性疾病中最被忽视的疾病之一。 撒哈拉非洲。尽管冈比亚疾病有望在2030年消除，但在冲突中的控制 而通常发生HAT的偏远地区仍然具有挑战性。罗得森氏病的中断并不是 然而，由于野生和家养动物储藏库的存在，目前仍在设想中。因为相关的采采赛- 传播的寄生虫也会在家畜中造成毁灭性的消耗性疾病，我们的研究也 改善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 最近关于治愈患者的治疗方法取得了进展，但预防疾病的工具箱仍然不足。近期 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的前沿 以防止在哺乳动物感染早期传播，当时唾液中引入的寄生虫非常少。 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一项 传播阻断疫苗(TBV)策略，针对通过采采树唾液传播的后环寄生虫。 目的1.了解唾液腺(SG)采采氏-锥虫对话的机制。我们的数据 提示锥虫感染改变了采采素SG基因的表达和唾液成分(唾液体)。至 了解寄生虫-SG分子对话，我们将：1)表征正常和 被感染的SGS，2)验证候选miRNAs在调节 感染性接种；3)确定寄生虫感染对SG生理和唾液的影响 天然采采子种群的组成。 目的2.描述亚环锥虫在咬合部位的传播特征，并阐明媒介衍生的因素 来协调这一过程。我们的数据表明，受感染的哺乳动物的不同组织中有不同的 血液中的种群形成锥虫。为了更好地了解介导寄生虫感染的因素 在哺乳动物宿主中的动力学，我们将确定：1)宿主-寄生虫在过程中的时空对话 从咬合处扩散到血液和外周器官；2)咬合处的免疫对话 与唾液中传播的多种因子(外体和唾液共生体)结合在一起。 目的3.研究阻止哺乳动物咬合部寄生虫发展的表面蛋白家族(Fam10) 地点。我们的研究鉴定了一个在MMC细胞表面表达的蛋白质家族(Fam10)，并证明了 针对一名Fam10成员接种疫苗可减少感染早期的寄生虫血症。评估其可行性 在TBV方法中，我们将：1)研究天然锥虫种群中Fam10蛋白的多样性；2) 筛选保守的免疫原肽，3)测试针对多个 保守的Fam10抗原，以及4)确定咬伤部位保护性免疫的决定因素。