West Nile Viral Determinants of Avian Pathogenesis

禽类发病机制的西尼罗河病毒决定因素

• 批准号: 7248050
• 负责人: Aaron Cole Brault
• 金额: $ 32.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248050
• 关键词: Address; American; Antiviral Agents; Australia; Birds; California; Cells; Chimera organism; Colorado; Complementary DNA; Crows; Culicidae; Data; Detection; Development; Disease; Disease Outbreaks; Dose; Ducks; Encephalitis; Encephalitis Viruses; Engineering; Epidemic; Epidemiological Factors; Epidemiology; Exposure to; Familiarity; Future; Generations; Genetic; Genetic Determinism; Genotype; Goals; High temperature of physical object; Human; In Vitro; Infection; Investigation; Kenya; Knowledge; Laboratories; Medical Surveillance; Methods; Modeling; Morbidity - disease rate; Mosquito-borne infectious disease; Mutagenesis; North America; Oral; Pathogenesis; Pathogenicity; Phenotype; Phylogenetic Analysis; Population; Prevention; Production; Qualifying; RNA; Replicon; Research; Research Personnel; Role; Sentinel; Standards of Weights and Measures; System; Temperature; Testing; Time; Tissues; United States; Universities; Vaccination; Vertebral column; Viral; Viral Antigens; Viremia; Virulence; Virulent; Virus; West Nile viral; West Nile virus; Work; animal facility; arbovirus disease; base; design; epizootic; experience; genetic element; insight; mortality; positional cloning; prevent; progenitor; programs; reconstruction; tissue tropism; transmission process; vaccine development; vector mosquito; virus genetics; wild bird

DESCRIPTION (provided by the applicant): Since its introduction in 1999, West Nile virus (WNV) has become the leading cause of arboviral encephalitis in the United States. The most notable epidemiological factors associated with the rapid emergence of WNV in North America have been the development of high viral titers within birds and mortality among wild bird populations. Despite the use of crow mortality as a sentinel for WNV activity, the underlying viral genetic basis for WNV pathogenicity in birds and the role of increased avian virulence in the transmission of WNV are poorly understood. Generation of fundamental data on the basis of replication within the WNV avian reservoir will fill a critical gap in our knowledge of WNV transmission and aid in the improvement of existing surveillance strategies and predictive emergence models for the prevention of human and veterinary disease. The hypothesis that the emergence of WNV within North America has been the result of the introduction of a new viral genotype capable of efficient avian replication will be addressed with the following research aims: (1) Identify WN viral genetic determinants responsible for differential crow virulence through the generation of viral chimeras between avian virulent and avirulent WNV strains. The resulting chimeras will be tested for their ability to produce high viremia and morbidity within crows as well as replicate at elevated temperatures in an in vitro replication system. (2) Elucidate differences in crow pathogenesis between WNVs in order to identify the pathogenic mechanism(s) that underlie differential avian Virulence. Tissue tropism, neuro-invasion and viral persistence will be correlated with specific genetic determinants. Mosquito infectivity will be assessed through the generation of a dose-infection model, allowing for the estimation of the time to which different chimeras will be infectious to mosquitoes. (3) Assess the potential for the emergence of alternative WNV genotypes through the incorporation of the minimal virulence determinants previously identified into alternative WN viral genetic backbones that have not been associated with avian mortality. Adaptation of avirulent WNV genotypes to crows will also be investigated to gauge selection for bird virulence as a mechanism for the emergence of the North American WNV genotype. Critical basic information on the role of viral replication and mechanisms that modulate virulence in natural viral populations within avian reservoir will allow for more efficient implementation of an vaccination programs and the prediction of future WNV outbreaks. In addition, fundamental knowledge of viral replication and pathogenesis will provide insight for the development of vaccine and antiviral strategies.

描述（由申请人提供）：自1999年引入以来，西尼罗河病毒（WNV）已成为美国弧病毒脑炎的主要原因。与北美WNV快速出现有关的最显着的流行病学因素是鸟类内部的高病毒滴度和野生鸟类人群中的死亡率的发展。尽管使用乌鸦死亡率作为WNV活性的前哨，但众所周知，鸟类中WNV致病性的潜在病毒遗传基础和增加的鸟类毒力在WNV传播中的作用知之甚少。基本数据基于WNV禽类储层中的复制，将填补我们对WNV传播的了解的关键空白，并有助于改善现有的监视策略和预防人类和兽医疾病的预测出现模型。以下研究的目的将解决北美WNV在北美内部的出现的假设，是引入了能够有效的鸟类复制的新病毒基因型的结果：（1）确定通过在雅芳和贪婪的Wnv strains之间产生病毒性嵌合体的差异遗传决定因素。所得的嵌合体将测试其在乌鸦内产生高病毒血症和发病率的能力，并在体外复制系统中的温度升高时复制。 （2）阐明WNV之间的乌鸦发病机理的差异，以确定依赖差异禽流量毒力的致病机制。组织的乳房，神经侵袭和病毒持久性将与特定的遗传决定因素相关。蚊子感染性将通过产生剂量感染模型来评估，从而估算不同嵌合体具有感染蚊子的时间。 （3）通过掺入以前鉴定为与禽死亡率没有相关的替代性WN病毒遗传骨架中的最小毒力决定因素来评估替代WNV基因型的出现的潜力。还将研究对乌鸦的无毒基因型的适应，以衡量鸟类毒力的选择，以此作为北美WNV基因型出现的一种机制。有关病毒复制和机制的作用的关键基本信息，这些机制调节了禽类储层中自然病毒种群中毒力的作用，将允许更有效地实施疫苗接种计划以及预测未来的WNV暴发。此外，病毒复制和发病机理的基本知识将为疫苗和抗病毒策略的发展提供洞察力。

项目成果

West Nile Virus Temperature Sensitivity and Avian Virulence Are Modulated by NS1-2B Polymorphisms.

• DOI: 10.1371/journal.pntd.0004938
• 发表时间: 2016-08
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Dietrich EA;Langevin SA;Huang CY;Maharaj PD;Delorey MJ;Bowen RA;Kinney RM;Brault AC
• 通讯作者: Brault AC