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Evolution and pathogenesis of Usutu virus, an emerging arbovirus

一种新兴虫媒病毒乌苏图病毒的进化和发病机制

基本信息

批准号：
10218381
负责人：
Nisha Duggal
金额：
$ 23.15万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218381
关键词：
Address Affect Africa African Americas Antibodies Arboviruses Area Attenuated Australia Blood Circulation Cells Chimera organism DNA Sequence Alteration Data Dengue Virus Disease Dose Encephalitis Epidemic Europe European Evolution Flavivirus Future Genes Genetic Genetic Crosses Genetic Determinism Goals Human Immune Immune response Immunoglobulin G Immunoglobulins Immunologic Factors In Vitro Infection Kunjin virus Lead Membrane Meningitis Modeling Mosquito-borne infectious disease Mus Mutation Pathogenesis Pathogenicity Point Mutation Prevention strategy Public Health Research Research Personnel Risk Role Serum System Testing Therapeutic Time Vaccines Viral Viral Pathogenesis Viremia Virulence Virus Virus Diseases West Nile virus Wild Type Mouse Work Zoonoses burden of illness cross reactivity human disease in vivo innovation mathematical model migratory bird mortality mosquito-borne mouse model neglect novel predictive modeling prevent programs reverse genetics tool development transmission process vaccine development vector virus genetics

项目摘要

Project Summary West Nile virus (WNV) and Usutu virus (USUV) are closely-related mosquito-borne viruses that cause neuroinvasive disease in humans. WNV emerged from African and Europe into the U.S. in 1999, and it is now the most common mosquito-borne disease in the continental U.S.; however, no vaccines or therapeutics are available. USUV is emerging in Europe, where it has been introduced at least three times from Africa by migratory birds, and human disease cases are increasing. The viral factors that lead to increases in flavivirus pathogenesis include naturally-occurring viral genetic mutations and cross-reactive antibodies from co- circulating heterologous flaviviruses. We have found that African and European strains of USUV differ drastically in the level of disease generated in a wild-type mouse model, with differences in viremia of up to 100-fold between USUV strains. We have also found that human WNV convalescent sera partially cross- neutralizes USUV in vitro. The long-term goal of this project is to understand the effect of viral evolution and antibody cross-reactivity on flavivirus emergence and disease. The objectives of this study are to identify the genetic mutations in USUV that dictate differences in pathogenesis and to determine whether WNV cross- reactive antibodies alter USUV disease. The hypothesis is that viral mutations acquired during emergence increase USUV pathogenesis and that heterologous WNV antibodies decrease USUV pathogenesis. Two specific aims will address this hypothesis: 1) Identify viral genetic determinants of USUV disease; and 2) Determine the impact of WNV antibodies on USUV disease. In the first aim, a reverse genetics system that we recently developed will be used to identify mutations in USUV that alter viremia and disease in mice. In the second aim, the effect of IgG purified from human WNV convalescent sera on USUV disease will be evaluated in vivo. The research proposed here is innovative because it investigates significant differences in pathogenesis caused by contemporary strains of an emerging, neglected virus using a novel reverse genetics system. Upon successful completion of the proposed research, the anticipated contribution of this work will be the identification of viral factors that affect USUV pathogenesis and host immune correlates of USUV disease. This contribution is expected to be significant because it will lead to the ability to develop therapeutics and vaccines to reduce flavivirus transmission and disease.

项目概要西尼罗河病毒（WNV）和乌苏图病毒（USUV）是密切相关的蚊媒病毒，可引起人类神经侵袭性疾病。西尼罗河病毒于 1999 年从非洲和欧洲进入美国，现在已美国大陆最常见的蚊媒疾病；然而，目前尚无疫苗或治疗方法可用的。 USUV 正在欧洲兴起，并已从非洲引进至少 3 次候鸟和人类疾病病例正在增加。导致黄病毒增加的病毒因素发病机制包括自然发生的病毒基因突变和来自共同的交叉反应抗体循环的异源黄病毒。我们发现非洲和欧洲的 USUV 品种有所不同野生型小鼠模型中产生的疾病水平显着增加，病毒血症的差异高达 USUV 品系之间相差 100 倍。我们还发现人类西尼罗河病毒恢复期血清部分交叉体外中和 USUV。该项目的长期目标是了解病毒进化的影响和抗体交叉反应对黄病毒的出现和疾病。本研究的目的是确定 USUV 中的基因突变决定了发病机制的差异，并确定 WNV 是否交叉反应性抗体改变 USUV 疾病。假设是病毒在出现期间获得突变增加 USUV 发病机制，异源 WNV 抗体减少 USUV 发病机制。二具体目标将解决这一假设：1）确定 USUV 疾病的病毒遗传决定因素；和 2) 确定 WNV 抗体对 USUV 疾病的影响。第一个目标是建立一个反向遗传学系统最近开发的技术将用于识别 USUV 中改变小鼠病毒血症和疾病的突变。在第二个目标，将评估从人WNV恢复期血清中纯化的IgG对USUV疾病的作用体内。这里提出的研究具有创新性，因为它调查了使用新型反向遗传学研究由一种新兴的、被忽视的病毒的当代菌株引起的发病机制系统。成功完成拟议的研究后，这项工作的预期贡献将是确定影响 USUV 发病机制的病毒因素以及 USUV 疾病的宿主免疫相关因素。预计这一贡献将是重大的，因为它将带来开发治疗方法和减少黄病毒传播和疾病的疫苗。