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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该提案的总体假设是，脊椎动物宿主中弧菌病毒感染的建立和过程。我们的工作假设是，将登革热病毒传播到埃及埃及蚊子的唾液腺，可修饰唾液腺中的蛋白质表达和预期的唾液，从而增强了病毒对人的传播性。 该假设是基于以下要求：登革热病毒必须传播到唾液腺，以便由原代蚊子载体AE传播。埃及[1]和蚊子可以以一种鼓励建立感染的方式改变叮咬遗址的当地环境 [2]。我们当时推断出一些唾液成分在进食后注入脊椎动物中，调节人类宿主中的登革热感染。我们的初步发现表明，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尚待研究。登革热病毒已显示与AE结合。埃及唾液腺和中肠蛋白[3-4]，这些组织中至少有一个登革热病毒受体[5]。但是，尚未研究在预期的唾液中是否有病毒结合蛋白，可以帮助病毒促成病毒以建立感染的靶向细胞。蚊子的唾液中含有多种鸡尾酒，包括药理学活性化合物，与病毒同时沉积在脊椎动物宿主的咬合部位[6]。其中一些人除了引起唾液特异性抗体的产生外，还导致人类淋巴细胞[7-8]和树突状细胞的稳态[7-8] [10]。这种细胞因子调节和唾液蛋白的先前存在抗体如何影响登革热从载体到脊椎动物的传播。我们建议研究登革热感染在蚊子载体的唾液腺蛋白谱上呈现的特定变化，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AE的免疫反应。埃及唾液蛋白以及这种反应是否改变了登革热病毒感染的过程。 具体目标 目标1：表征来自AE的唾液和唾液腺提取物的差异蛋白表达。登革热感染和未感染的蚊子之间的埃及。 H0：将登革热病毒传播到蚊子唾液腺改变了改变的蛋白质特征 唾液和唾液腺。 目标2：鉴定唾液和唾液腺提取物中的蛋白质，能够与登革热病毒和人类免疫细胞（如淋巴细胞和树突状细胞（DC））结合。 H0：根据感染状态差异表达的蚊子唾液蛋白可能结合登革热病毒和人类淋巴细胞，从而增强了登革热的潜力 靶向免疫细胞。 目标3：表征脊椎动物宿主对AE的免疫反应。埃及唾液蛋白以及该反应对登革热感染的影响。 H0：先天性免疫反应和对蚊子唾液蛋白的先前存在的抗体会影响登革热从蚊子载体到脊椎动物的传播成功。蚊子中的登革热病毒感染通过减少唾液蛋白的调节来改变这些免疫反应。