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.

这种应用程序是对人类非洲锥虫病（HAT），一个最被忽视的疾病， 撒哈拉非洲。尽管预计到2030年将消除冈比亚病， 而HAT通常发生的偏远地区仍然具有挑战性。罗得西亚病的中断不是 然而，由于野生动物和家畜水库的存在，在这个时候还可以想象。因为采采蝇- 传播的寄生虫也会导致家畜的毁灭性消耗疾病，我们的研究也表明， 改善非洲大陆的养分供应和农业生产力。虽然取得了很大进展， 虽然最近对治疗病人的疗法进行了研究，但预防疾病的工具箱仍然不够。最近 哺乳动物咬痕生物学的发现为新方法的发展开辟了新的领域 以防止在哺乳动物感染的早期传播，此时唾液中引入的寄生虫很少。 在这里，我们将建立在分子和免疫学对话的基础上， 最终影响咬伤部位的疾病进展。这些信息将有助于评估一个 传播阻断疫苗（TBV）策略，目标是通过采采蝇唾液传播的亚循环寄生虫。 目标1.了解舌蝇与锥虫在唾液腺对话的机制基础。我们的数据 表明锥虫感染改变了采采蝇SG基因表达和唾液组分（唾液蛋白组）。到 了解寄生虫-SG分子对话，我们将：1）表征正常和 感染的SG，2）验证候选miRNA在调节感染的SG中的产物中的功能参与， 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 天然采采蝇种群的组成。 目标2.描述在叮咬部位的亚循环锥虫播散并阐明媒介衍生因子 来协调这个过程。我们的数据表明，受感染哺乳动物的不同组织具有不同的 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， 在哺乳动物宿主的动态，我们将确定：1）时间和空间的宿主-寄生虫对话期间 从叮咬部位向血液和外周器官的传播，以及2）叮咬处的免疫对话 位点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.研究一个表面蛋白家族（Fam 10）在哺乳动物叮咬处阻断寄生虫发育 绝佳的价钱我们的研究鉴定了mMC细胞表面表达的一个蛋白家族（Fam 10），并证明了 针对一个Fam 10成员的疫苗接种可以减少感染早期的寄生虫血症。评估可行性 在TBV方法中，我们将：1）研究自然锥虫种群中Fam 10蛋白的多样性，2） 筛选保守的免疫原性肽，3）测试靶向多个免疫原性肽的肽抗体的疫苗效力， 保守的Fam 10抗原，以及4）确定咬伤部位保护性免疫的决定因素。