权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结