Vector-Borne Diseases: Biology Of Vector Host Relationship

媒介传播疾病：媒介宿主关系的生物学

• 批准号: 8745364
• 负责人: Jose Ribeiro
• 金额: $ 122.38万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745364
• 关键词: Africa; Animals; Anopheles gambiae; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Antigens; Arthropod Vectors; Arthropods; Biodiversity; Bioinformatics; Biological; Biological Assay; Biology; Blood; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Cell Line; Chagas Disease; Chemicals; Chiroptera; Coagulation Process; Collaborations; Complement; Complex; Culicidae; Dancing; Disease; Drosophila genus; Ecology; Epidemiology; Eukaryotic Cell; Evolution; Extramural Activities; Family; Felis catus; Fleas; Flying body movement; Future; Gene Expression Profile; Genes; Genome; Gland; Goals; Greek; Helminths; Hemorrhage; Hemostatic Agents; Hemostatic function; Immune; Immune response; Immune system; Individual; Infection; Injury; Insecta; Knowledge; Learning; Legal patent; Leishmaniasis; Magic; Malaria; Maps; Methods; Mining; Molecular Biology; Organism; Paper; Peptides; Pharmacologic Substance; Phospholipids; Physiological Processes; Plasmodium falciparum; Platelet aggregation; Process; Property; Protein Family; Proteins; Publications; Puncture procedure; Rabies; Race; Reaction; Reporting; Research; Research Personnel; Saliva; Salivary; Salivary Glands; Salivary Proteins; Sand Flies; Scientist; Sex Attractants; Simuliidae; Site; Skin; South America; Structure; System; Techniques; Ticks; Trypanosoma cruzi; Vaccines; Vasodilator Agents; Vector-transmitted infectious disease; Virulence; Work; arm; cDNA Library; feeding; in vitro testing; in vivo; insight; interest; male; member; novel; pathogen; pressure; prevent; programs; structural biology; success; sucking; transmission process; vaccine development; vasoconstriction; vector

Summary: (500-7900 characters long) Vector arthropods, such as mosquitoes, triatomine bugs and ticks, salivate while they puncture our skin in their search of blood. This saliva contains dozens to hundreds of compounds that have anti-clotting, anti-platelet, vasodilatory, anti-inflammatory, and immunomodullatory functions. While helping the vector to feed, it also modifies the site where pathogens are injected and in many cases facilitates the infection process. For this reason, salivary proteins of vectors can be used as vaccine targets for the diseases they transmit. Salivary proteins can also be used as immuno-epidemiological markers of vector exposure, and in themselves can have potent and novel pharmacological activities. Because the saliva of hematophagous animals is under attack of their host's immune system, their constituents are under a rapid evolutionary pressure in an arms' race scenario with their hosts, causing an enormous variety of unique protein families even in closely related organisms. The section of vector biology aims at uncovering the biodiversity of salivary proteins in the near 500 genera of blood sucking arthropods, and to discover the function of the novel protein families that we encounter. Accordingly we have developed a two pronged approach focusing in sialotranscriptome discovery projects and functional sialomic studies. In addition to these core studies on the saliva of vector arthropods, the section also collaborated with other members of the LMVR and other extramural scientists lending its expertise in bioinformatics, structural biology and vascular biology. Dr. Ribeiro's interest in vector ecology also led to continuing work on the ecology of malaria vectors in Africa. In the current fiscal year (2013), members of the Section of Vector Biology contributed to a total of 14 papers and 1 patent application. Sialotranscriptome discovery projects: Because host hemostasis (the physiological process that prevents blood loss, consisting of platelet aggregation, blood clotting and vasoconstriction) is a complex and redundant phenomenon, the salivary glands of blood sucking arthropods consist of a magic potion with diverse chemicals that in a redundant way counteract host mechanisms to prevent blood loss, allowing the fast acquisition of a meal. Salivary transcriptome made in the past few years indicate that the magic potion consists of 70-100 different proteins in the case of mosquitoes, for example, to over 1,000 in the case of ticks (Ticks feed for several days and have to disarm host immune reactions, in addition to the hemostatic system). Transcriptome studies also show that the salivary proteins of blood sucking arthropods are at a very fast pace of evolution, perhaps explaining why every genera studied so far has several unique protein families. Indeed there are unique proteins found at the subgenus level. Given we can now describe in detail the sialotranscriptome (from the Greek word sialo = saliva) of a single organism, we can ask now what is the universe of salivary proteins associated to blood feeding, the so called sialoverse. There are near 19,000 species of blood sucking arthropods in 500 different genera. If we find (minimally) 5 novel protein families per genus (within the 70-500 proteins in each sialome), there are at least 2,500 novel proteins to be discovered, each one with an interesting pharmacological property. We have so far explored less than 20 genera of blood sucking arthropods, and it is our goal to extend sialotranscriptome discovery to map this pharmacological mine for future studies, and in the process learn the paths taken by genomes in their evolution to blood feeding, and identify proteins with pharmacological and vaccine potential. In the current fiscal years, we produced four papers related to sialotranscriptome discovery, including two for sand fly vectors of Leishmaniasis (1-2), in collaboration with Dr. Jesus Valenzuela, one for the cat flea (3) and one from the vampire bat Desmodus rotundus, a vector of rabies (4). Novel protein families were discovered in fleas and vampire bats. Functional studies: We advanced our knowledge regarding the function of vector salivary proteins as reported in 2 publications, one describing a novel function for a member of the salivary antigen 5 family (5) and another describing the crystal structure of an anti-inflammatory protein from a triatomine bug (6). We have also collaborated in the functional identification of glycoinositol-phospholipids from Trypanosoma cruzi, the causative agent of Chagas disease (7). Bioinformatic collaborations: Dr. Ribeiro collaborated with intra and extra mural investigators lending his expertise in bioinformatics, helping to functionally characterize and annotate the genomes of a parasitic worm (8) and the main malaria vector of South America (9), the sex-pheromone gland transcriptome of a sand fly vector of leishmaniasis (10), the male accessory gland sexual transcriptome of a fruit fly (11), and the expression of virulence genes in Plasmodium falciparum (12), the main malaria pathogen. Vector ecology Studies related to Anopheles gambiae swarming were concluded, describing the dance of male mosquitoes (13) as well as a methodological approach to quantify stereoscopy videos of mosquitoes flying at twilight (14). Patent application: Dr. Francischetti submitted a patent application for an anticoagulant discovered in a black fly (15).

摘要：（500-7900 个字符长） 媒介节肢动物，如蚊子、锥蝽和蜱虫，在刺穿我们的皮肤寻找血液时会流口水。这种唾液含有数十至数百种具有抗凝血、抗血小板、血管舒张、抗炎和免疫调节功能的化合物。在帮助媒介进食的同时，它还改变了病原体注入的部位，在许多情况下促进了感染过程。 因此，载体的唾液蛋白可以用作其传播的疾病的疫苗靶标。唾液蛋白还可以用作载体暴露的免疫流行病学标志物，并且其本身可以具有有效且新颖的药理活性。 由于食血动物的唾液受到宿主免疫系统的攻击，它们的成分在与宿主的军备竞赛中承受着快速进化的压力，甚至在密切相关的生物体中也会产生大量独特的蛋白质家族。载体生物学部分旨在揭示近 500 个吸血节肢动物属的唾液蛋白的生物多样性，并发现我们遇到的新蛋白家族的功能。因此，我们开发了一种双管齐下的方法，重点关注唾液转录组发现项目和功能性唾液酸组学研究。 除了这些关于媒介节肢动物唾液的核心研究外，该部门还与 LMVR 的其他成员和其他校外科学家合作，提供其在生物信息学、结构生物学和血管生物学方面的专业知识。里贝罗博士对媒介生态学的兴趣也导致了他对非洲疟疾媒介生态学的持续研究。 在本财年（2013），媒介生物学组成员共发表了14篇论文和1项专利申请。 唾液酸转录组发现项目： 由于宿主止血（防止失血的生理过程，包括血小板聚集、血液凝固和血管收缩）是一种复杂而多余的现象，吸血节肢动物的唾液腺由一种含有多种化学物质的神奇药水组成，这些化学物质以多余的方式抵消防止失血的宿主机制，允许快速获取食物。过去几年的唾液转录组表明，对于蚊子来说，这种神奇的药水由 70-100 种不同的蛋白质组成，例如，对于蜱虫来说，有超过 1,000 种蛋白质（蜱虫会进食数天，并且必须解除宿主的免疫反应） ，除了止血系统）。转录组研究还表明，吸血节肢动物的唾液蛋白进化速度非常快，这或许可以解释为什么迄今为止研究的每个属都有几个独特的蛋白质家族。事实上，在亚属水平上发现了独特的蛋白质。鉴于我们现在可以详细描述单个生物体的 sialotranscriptome（来自希腊语 sialo = 唾液），我们现在可以问与血液喂养相关的唾液蛋白宇宙是什么，即所谓的 sialoverse。吸血节肢动物有 500 个不同属，近 19,000 种。如果我们（至少）在每个属中发现 5 个新蛋白质家族（每个 sialome 中的 70-500 个蛋白质），则至少有 2,500 个新蛋白质有待发现，每个蛋白质都具有有趣的药理学特性。到目前为止，我们已经探索了不到 20 个吸血节肢动物属，我们的目标是扩展唾液转录组的发现，为未来的研究绘制这个药理学矿藏，并在此过程中了解基因组在进化到吸血方面所采取的路径，以及识别具有药理学和疫苗潜力的蛋白质。 在当前财政年度，我们发表了四篇与唾液转录组发现相关的论文，其中两篇是与 Jesus Valenzuela 博士合作的关于利什曼病沙蝇载体的论文 (1-2)，一篇是关于猫跳蚤的论文 (3)，一篇是关于吸血鬼的论文蝙蝠 Desmodus rotundus，狂犬病媒介 (4)。在跳蚤和吸血蝙蝠中发现了新的蛋白质家族。 功能研究： 我们推进了关于载体唾液蛋白功能的知识，如 2 篇出版物中所报道的那样，其中一篇描述了唾液抗原 5 家族 (5) 成员的新功能，另一篇描述了来自锥蝽的抗炎蛋白的晶体结构（6）。我们还合作对克氏锥虫（恰加斯病的病原体）的糖肌醇磷脂进行功能鉴定 (7)。 生物信息学合作： Ribeiro 博士与校内和校外研究人员合作，利用他在生物信息学方面的专业知识，帮助对寄生蠕虫 (8) 和南美洲主要疟疾载体 (9) 的基因组进行功能表征和注释，即疟疾的性信息素腺转录组。利什曼病的沙蝇载体 (10)、果蝇的雄性副腺性转录组 (11) 以及疟原虫毒力基因的表达恶性疟原虫 (12)，主要疟疾病原体。 矢量生态学 与冈比亚按蚊群聚相关的研究已经结束，描述了雄性蚊子的舞蹈 (13) 以及量化黄昏时飞行的蚊子立体视频的方法 (14)。 专利申请： Francischetti 博士提交了一份在黑蝇中发现的抗凝剂的专利申请 (15)。