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

• 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
• 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

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.

项目摘要 西尼罗河病毒（WNV）和USUTU病毒（USUV）是引起蚊子传播的病毒 人类的神经侵袭性疾病。 WNV于1999年从非洲和欧洲出现到美国，现在是 美国大陆上最常见的蚊子传播疾病；但是，没有疫苗或治疗药 可用的。 USUV正在欧洲出现，在欧洲，它已从非洲至少从非洲引入了三次 候鸟和人类疾病病例正在增加。导致黄酮病毒增加的病毒因素 发病机理包括自然发生的病毒遗传突变和来自共同反应的抗体 循环异源黄病毒。我们发现非洲和欧洲的USUV菌株有所不同 在野生型小鼠模型中产生的疾病水平上急剧，病毒血症的差异 USUV菌株之间的100倍。我们还发现，人类WNV疗养血清部分交叉 在体外中和usuv。该项目的长期目标是了解病毒进化的影响和 黄病毒出现和疾病的抗体交叉反应。这项研究的目标是确定 USUV中的基因突变决定发病机理的差异并确定WNV是否交叉 反应性抗体会改变USUV疾病。假设是出现期间获得的病毒突变 增加了USUV发病机理，并且异源WNV抗体可降低USUV发病机理。二 具体目的将解决这一假设：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。在第一个目标中，我们是我们的反向遗传系统 最近开发的将用于识别改变小鼠病毒血症和疾病的USUV中的突变。在 第二个目的，将评估从人类WNV康复血清纯化的IgG对USUV疾病的影响 体内。这里提出的研究具有创新性，因为它研究了 由新兴的，被忽视的病毒的当代菌株使用新型反向遗传学引起的发病机理 系统。成功完成拟议的研究后，这项工作的预期贡献将是 影响USUV发病机理和宿主免疫相关的病毒因子的鉴定。 预计这项贡献将是重要的，因为它将导致发展治疗学和 疫苗减少黄病毒的传播和疾病。