ENHANCEMENT OF DENGUE VIRUS TRANSMISSION DUE TO SALIVARY PROTEINS OF ITS VECTOR

由于其载体的唾液蛋白而增强登革热病毒的传播

• 批准号: 8359779
• 负责人: Christopher Mores
• 金额: $ 22.06万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359779
• 关键词: Aedes; Affect; Antibodies; Antibody Formation; Arbovirus Infections; Arthropods; Binding; Binding Proteins; Bite; Cells; Culicidae; Dendritic Cells; Dengue; Dengue Virus; Deposition; Down-Regulation; Environment; Funding; Grant; Homeostasis; Human; Immune; Immune Targeting; Immune response; Infection; Infectious Diseases Research; Lymphocyte; Midgut; Molecular Chaperones; National Center for Research Resources; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Saliva; Salivary; Salivary Glands; Salivary Proteins; Site; Source; Tissues; United States National Institutes of Health; Virus; Virus Diseases; Virus Receptors; Work; base; cost; cytokine; feeding; protein expression; protein profiling; response; success; transmission process; vector; vector mosquito

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall hypothesis of this proposal is that arthropod-expectorated proteins modulate the establishment and course of arboviral infections in the vertebrate host. Our working hypothesis is that dissemination of dengue virus to the salivary glands of Aedes aegypti mosquitoes modifies protein expression in the salivary glands and the expectorated saliva, thereby enhancing the transmissibility of the virus to people. This hypothesis is based on the requirement that dengue virus must disseminate into the salivary glands in order to be transmitted by the primary mosquito vector, Ae. aegypti [1] and that mosquito saliva can alter the local environment at the bite site in a way that encourages the establishment of an infection [2]. We infer then that some salivary components, injected into the vertebrate upon feeding, modulate the dengue infection in the human host. Our preliminary findings suggest that dengue infection alters the protein profile of the mosquito salivary glands. The sequencing and identification of these proteins and their possible roles in transmission remains to be investigated. Dengue virus has been shown to bind Ae. aegypti salivary gland and midgut proteins [3-4] and that there is at least one dengue virus receptor in these tissues [5]. However, whether there are virus binding proteins in the expectorated saliva, which could assist in the chaperoning of virus to target cells for the establishment of infection, has not been investigated. The saliva of mosquitoes contains a diverse cocktail of pharmacologically active compounds that are deposited simultaneously with virus to the bite site of the vertebrate host [6]. Some of these are responsible for the disruption of the homeostasis of human lymphocytes [7-8] and dendritic cells [9] in addition to eliciting saliva-specific antibody production [10]. How such cytokine modulation and preexisting antibodies to salivary proteins affect transmission of dengue from the vector to the vertebrate remains to be studied. We propose to investigate the specific changes that dengue infection renders on the salivary gland protein profile of the mosquito vector and how these changes affect the establishment of infection in vertebrate cells. Furthermore we will evaluate the immune response of the vertebrate to Ae. aegypti salivary proteins and whether this response alters the course of dengue virus infection. Specific Aims Aim 1: To characterize differential protein expression of saliva and salivary gland extract from Ae. aegypti between dengue-infected and uninfected mosquitoes. H0: Dissemination of dengue virus to the mosquito salivary glands changes the protein profile of the saliva and salivary glands. Aim 2: To identify proteins in mosquito saliva and salivary gland extract capable of binding to dengue virus and human immune cells such as lymphocytes and dendritic cells (DC). H0: Mosquito salivary proteins differentially expressed based on infection status may bind dengue virus and human lymphocytes, thereby enhancing the potential for dengue to establish replication in target immune cells. Aim 3: To characterize the vertebrate host immune response to Ae. aegypti salivary proteins, and the impact of that response on dengue infection. H0: Innate immune responses and preexisting antibodies to mosquito salivary proteins affect the transmission success of dengue from the mosquito vector to the vertebrate. Dengue virus infection in the mosquito alters these immune responses through down regulation of salivary proteins.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该提议的总体假设是节肢动物排泄蛋白调节脊椎动物宿主中虫媒病毒感染的建立和过程。我们的工作假设是，登革热病毒传播到埃及伊蚊的唾液腺会改变唾液腺和咳出唾液中的蛋白质表达，从而增强病毒向人类的传播能力。 该假设基于登革热病毒必须传播到唾液腺才能通过主要蚊子媒介伊蚊传播的要求。埃及伊蚊 [1] 并且蚊子唾液可以改变叮咬部位的局部环境，从而促进感染的发生 [2]。然后我们推断，在进食时注入脊椎动物的一些唾液成分可以调节人类宿主的登革热感染。我们的初步研究结果表明，登革热感染改变了蚊子唾液腺的蛋白质谱。这些蛋白质的测序和鉴定及其在传播中可能的作用仍有待研究。登革热病毒已被证明可以结合AE。埃及伊蚊唾液腺和中肠蛋白 [3-4]，并且这些组织中至少存在一种登革热病毒受体 [5]。然而，尚未研究吐出的唾液中是否存在病毒结合蛋白，从而帮助病毒陪伴至靶细胞以建立感染。蚊子的唾液含有多种药理活性化合物，这些化合物与病毒同时沉积到脊椎动物宿主的叮咬部位[6]。其中一些除了引起唾液特异性抗体产生外，还导致人类淋巴细胞[7-8]和树突状细胞[9]的稳态破坏[10]。这种细胞因子调节和预先存在的唾液蛋白抗体如何影响登革热从载体到脊椎动物的传播仍有待研究。我们建议研究登革热感染对蚊子载体唾液腺蛋白谱的具体变化，以及这些变化如何影响脊椎动物细胞中感染的建立。此外，我们将评估脊椎动物对伊蚊的免疫反应。埃及伊蚊唾液蛋白以及这种反应是否会改变登革热病毒感染的过程。 具体目标 目标 1：表征伊蚊唾液和唾液腺提取物的差异蛋白表达。感染登革热和未感染登革热的蚊子之间的埃及伊蚊。 H0：登革热病毒向蚊子唾液腺的传播改变了蚊子唾液腺的蛋白质谱 唾液和唾液腺。 目标 2：鉴定蚊子唾液和唾液腺提取物中能够与登革热病毒和淋巴细胞和树突状细胞 (DC) 等人类免疫细胞结合的蛋白质。 H0：根据感染状态差异表达的蚊子唾液蛋白可能会结合登革热病毒和人类淋巴细胞，从而增强登革热病毒在体内复制的潜力。 靶向免疫细胞。 目标 3：表征脊椎动物宿主对伊蚊的免疫反应。埃及伊蚊唾液蛋白，以及该反应对登革热感染的影响。 H0：先天免疫反应和针对蚊子唾液蛋白的预先存在的抗体影响登革热从蚊子媒介到脊椎动物的传播成功。蚊子感染登革热病毒会通过下调唾液蛋白来改变这些免疫反应。