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Arbovirus midgut escape mechanisms

虫媒病毒中肠逃逸机制

基本信息

批准号：
8777084
负责人：
Alexander W E Franz
金额：
$ 65.85万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777084
关键词：
Address Aedes Affect Alphavirus Apoptosis Apoptotic Arboviruses Arthropod Vectors Arthropods Baculoviruses Basal lamina Biochemical Biochemical Reaction Biological Assay Biology Blood Bypass Candidate Disease Gene Caspase Cell Death Cells Cleaved cell Culicidae DNA Dengue Dengue Virus Development Ensure Epithelium Exhibits Female Fibroblast Growth Factor Gene Silencing Gene Targeting Genes Genetic Recombination Health Immune Immunohistochemistry In Vitro Induction of Apoptosis Infection Ingestion Insect Vectors Insecta Invaded Lead Measures Metalloproteases Methods Microscopy Midgut Organ Pathway interactions Peptide Hydrolases Phenotype Physical condensation Play Process Production Proteins RNA Interference Regulator Genes Research Personnel Role Salivary Glands Secondary to Signal Transduction Sindbis Virus Site System Systemic infection TdT-Mediated dUTP Nick End Labeling Assay Techniques Testing Tissues Trachea Transgenic Organisms Transmission Electron Microscopy Up-Regulation Viral Virus Virus Diseases Virus Replication West Nile virus Work Yellow Fever chikungunya gain of function human morbidity human mortality in vitro testing in vivo inhibitor/antagonist interest novel overexpression research study success transmission process vector vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Arboviruses cause a significant world-wide health burden, with well over 100 million people becoming infected each year with viruses such as dengue, West Nile, yellow fever, and chikungunya, among others. Arboviruses are transmitted by arthropod vectors such as mosquitoes that become infected after ingestion of a viremic blood meal from a vertebrate host. Transmission to a new host requires that the arbovirus replicate in the midgut cells of the vector and then spread to secondary tissues eventually reaching the salivary glands. Once the latter are infected, the arthropod is able to transmit the virus to a new host. A long standing question in the field of vector biology is how arboviruses escape from the midgut, bypassing barriers such as basal laminae as well as host immune mechanisms. In some cases, arboviruses are able to infect and replicate in midgut epithelium but are not able to disseminate to other organs. The existence of this so-called midgut escape barrier implies that virus midgut escape is an active process. However, the mechanisms involved in midgut escape by arboviruses are almost completely unknown. This proposal addresses the signaling mechanisms used by the mosquito-borne viruses dengue, chikungunya, and Sindbis viruses to escape the midgut. Previous work by the investigators has defined a novel mechanism used by baculovirus to escape the midgut of their insect host. Baculoviruses use an elegant mechanism that signals a stepwise cascade of protease activation, wherein matrix metalloproteases become activated and in turn activate effector caspases, which directly cleave components of the basal lamina. This leads to remodeling of the basal lamina which lines tracheal cells associated with the midgut and culminates in the establishment of efficient systemic infections. The hypothesis underlying this proposal is that mosquito-borne arboviruses utilize this same pathway for midgut escape, and preliminary results support this hypothesis. Specifically, (1) it will be determined whether the mechanisms used by baculoviruses to remodel the midgut barrier are also utilized by arboviruses, including activation of matrix metalloproteases and caspases; (2) the contribution of candidate genes involved in midgut escape will be evaluated by RNA interference, arbovirus transducing systems, and transgenic Aedes aegypti mosquitoes by silencing or overexpressing target genes; and (3) the contribution of apoptosis and key apoptotic regulatory genes to arbovirus midgut escape will be tested. The results of these studies will contribute important new information to the understanding of arbovirus-vector interactions and potentially lead to new strategies for control of arbovirus transmission in the field.

描述（由申请人提供）：虫媒病毒造成了严重的全球健康负担，每年有超过1亿人感染登革热、西尼罗河、黄热病和基孔肯雅热等病毒。虫媒病毒通过节肢动物媒介传播，如蚊子，在摄入来自脊椎动物宿主的病毒血餐后被感染。传播到新的宿主需要虫媒病毒在载体的中肠细胞中复制，然后传播到次级组织，最终到达唾液腺。一旦后者被感染，节肢动物能够将病毒传播到新的宿主。在媒介生物学领域长期存在的问题是虫媒病毒如何从中肠逃逸，绕过屏障，如基底层以及宿主免疫机制。在某些情况下，虫媒病毒能够感染中肠上皮细胞并在其中复制，但不能传播到其他器官。这种所谓的中肠逃逸屏障的存在意味着病毒中肠逃逸是一个主动过程。然而，虫媒病毒中肠逃逸的机制几乎完全未知。该提案解决了蚊媒病毒登革热，基孔肯雅和辛德毕斯病毒逃避中肠的信号机制。研究人员先前的工作已经确定了杆状病毒逃离昆虫宿主中肠的一种新机制。杆状病毒使用一种优雅的机制，该机制发出蛋白酶激活的逐步级联信号，其中基质金属蛋白酶被激活，进而激活效应物半胱天冬酶，其直接切割基底层的组分。这导致基底层的重塑，基底层内衬与中肠相关的气管细胞，并在建立有效的全身感染中达到高潮。这一假设的基础是，蚊媒虫媒病毒利用这一相同的途径进行中肠逃逸，初步结果支持这一假设。具体而言，（1）将确定杆状病毒用于重塑中肠屏障的机制是否也被虫媒病毒利用，包括基质金属蛋白酶和半胱天冬酶的活化;（2）将通过RNA干扰、虫媒病毒转导系统和通过沉默或过表达靶基因的转基因埃及伊蚊来评估参与中肠逃逸的候选基因的贡献;以及（3）将测试细胞凋亡和关键细胞凋亡调控基因对虫媒病毒中肠逃逸的贡献。这些研究的结果将有助于重要的新信息，了解虫媒病毒的相互作用，并可能导致新的战略控制虫媒病毒的传播领域。