Evaluation of the Effects of Chikungunya N-linked Glycosylation on Pathogenesis

基孔肯雅热 N 联糖基化对发病机制影响的评估

基本信息

批准号：
8457220
负责人：
Charles Edwin McGee
金额：
$ 2.13万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2013-06-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457220
关键词：
Aedes Africa Alphavirus Animal Model Arthralgia Arthritis Arthropods C Type Lectin Receptors C-Type Lectins C57BL/6 Mouse Caribbean region Cell physiology Cells Chikungunya virus Chronic Complex Coupled Culicidae Data Dendritic Cells Development Disease Effector Cell Epidemic Europe Evaluation Expression Library Fever Genes Genetic Glycoproteins Goals Human Immune Immune response In Vitro India Indian Ocean Islands Individual Infection Inflammation Inflammatory Inflammatory Response Integration Host Factors Interferons Joints Lectin Receptors Limb structure Link Mediating Mediator of activation protein Mus Muscle Myositis Nature Pathogenesis Pathology Pathway interactions Pattern Phenotype Polyarthralgias Polysaccharides Population Post-Translational Protein Processing Preparation Production Proteins Public Health RNA Viruses Replicon Research Rheumatoid Arthritis Role Ross river virus Signal Transduction Signaling Protein Southeastern Asia Swelling Therapeutic Tropism United States Vaccines Viral Viral Proteins Virion Virus Virus Diseases base burden of illness cell type chikungunya combat cytokine design gene induction glycosylation human disease human morbidity human mortality immune activation in vivo lymph nodes mutant new therapeutic target particle positional cloning public health relevance receptor research study response screening sugar therapeutic target therapy development transmission process vector control vector mosquito vector transmission virus envelope virus host interaction virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Alphaviruses are a significant cause of human morbidity and mortality with arthropod-borne transmission of these agents resulting in thousands of debilitating infections per annum. Chikungunya virus (CHIKV) is significant public health concern; recently characterized genetic adaptation has allowed this virus to efficiently utilize Aedes albopictus mosquitoes, which are now distributed worldwide, as a primary transmission vector [1,2]. As such, in recent years epidemic transmission of CHIKV has resulted in millions of human infections in Africa, the Indian Ocean islands, India, and Southeast Asia [3-9] as well as the importation of human cases into the United States, the Caribbean, and Europe [8]. In some instances this has been followed by localized transmission cycles [10]. Classical vector control has been the primary strategy to combat mosquito-borne viruses; however, population expansion of mosquito vectors, coupled with a lack of vaccines serves to emphasize the need for the development of alternate anti-viral therapeutic targets. However, interactions between CHIKV and the vertebrate innate immune response that mediate clearance and pathogenesis remain poorly defined. The long-term goal of this research is to use reverse genetics and small animal models of inflammatory arthritis to identify viral and host factors that drive alphavirus-induced disease. The objective of this application is to identify specific interactions between CHIKV envelope glycans and host C-type lectin receptors and elucidate the consequence of those interactions on innate immune cell tropism, signaling, and function. Toward this goal the following specific aims are proposed: Specific Aim 1: To analyze the role of CHIKV N-linked glycans in modulating CHIKV infection and inflammatory gene induction in vivo and in vitro. Specific Aim 2: To identify specific C-type lectin receptors that interact with CHIKV envelope/virion N-linked glycans. We hypothesize that CHIKV pathogenesis is immune mediated and results from stimulation of innate immune activation via interactions between viral N-linked glycans and host C-type lectins. Experiments have been designed to identify specific interactions between a panel of CHIKV deficient for known glycans and an expression library of host C-type lectins. Additionally, these viruses will be evaluated in vitro and in vivo toward characterizing the effects of CHIKV glycans on inflammation, pathogenesis, and innate immune activation and cytokine production. The proposed studies are highly significant to the development of CHIKV anti-viral therapeutics as they will directly assess the interactions between viral and host factors that stimulate protective and pathogenic responses and as such may identify novel therapeutic targets.

描述（由申请人提供）：α病毒是人类发病率和死亡率的重要原因，这些药物的传播这些药物的传播导致每年数千种令人衰弱的感染。基孔肯雅病毒（CHIKV）是公共卫生的重大关注；最近对遗传适应性的表征使该病毒能够有效利用埃德斯白化蚊子（现在是全球范围内分布的）作为主要的传输载体[1,2]。因此，近年来，CHIKV的流行传播导致非洲，印度洋群岛，印度和东南亚的数百万人类感染[3-9]，以及将人类病例进口到美国，加勒比海和欧洲[8]。在某些情况下，随后是局部传输周期[10]。经典载体控制一直是打击蚊子传播病毒的主要策略。然而，蚊子载体的种群扩大，再加上缺乏疫苗，可以强调开发替代抗病毒治疗靶标的需求。然而，CHIKV与脊椎动物先天免疫反应之间的相互作用，介导清除和发病机理的定义仍然很差。这项研究的长期目标是使用反向遗传学和炎症性关节炎的小动物模型来鉴定驱动α病毒引起疾病的病毒和宿主因素。该应用的目的是确定Chikv包膜聚糖和宿主C型凝集素受体之间的特定相互作用，并阐明这些相互作用在先天免疫细胞质量，信号传导和功能上的结果。为此，提出了以下特定目的：具体目的1：分析Chikv N连接的聚糖在调节Chikv感染和体内和体外炎症基因诱导中的作用。特定目的2：确定与CHIKV相互作用的特定C型凝集素受体信封/病毒体N连接的聚糖。我们假设CHIKV发病机理是免疫介导的，并且是由于病毒N-连接聚糖和宿主C型凝集素之间的相互作用而刺激先天免疫激活的原因。已经设计了实验，以确定缺乏已知聚糖和宿主C型凝集素的表达库之间的CHIKV小组之间的特定相互作用。此外，将在体外和体内评估这些病毒，以表征Chikv Glycans对炎症，发病机理以及先天免疫激活和细胞因子产生的影响。拟议的研究对于CHIKV抗病毒疗法的发展至关重要，因为它们将直接评估刺激保护性和致病反应的病毒和宿主因素之间的相互作用，因此可能会确定新的治疗靶标。