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）已成为美国虫媒病毒性脑炎的主要原因。与西尼罗河病毒在北美迅速出现有关的最显著的流行病学因素是鸟类体内病毒滴度高和野生鸟类种群死亡率高。尽管使用乌鸦死亡率作为WNV活动的哨兵，但对WNV在鸟类中致病性的潜在病毒遗传基础以及WNV传播中禽类毒力增加的作用知之甚少。在复制的基础上产生的基础数据在西尼罗河病毒的鸟类水库将填补我们的知识的一个关键的差距，西尼罗河病毒的传播和援助，在改善现有的监测战略和预测出现模型，以预防人类和兽医疾病。假设西尼罗河病毒在北美的出现是一种新的病毒基因型的引入，能够有效的鸟类复制的结果，将解决以下研究目标：（1）确定WN病毒的遗传决定因素，负责不同的乌鸦毒力，通过产生之间的病毒嵌合体禽强毒和无毒的西尼罗河病毒株。将测试所得嵌合体在乌鸦内产生高病毒血症和发病率的能力，以及在体外复制系统中在高温下复制的能力。(2)阐明西尼罗河病毒之间乌鸦发病机制的差异，以确定差异禽类毒力的致病机制。组织嗜性、神经侵袭和病毒持久性将与特定的遗传决定因素相关。将通过生成剂量-感染模型来评估蚊子感染性，从而估计不同嵌合体对蚊子具有感染性的时间。(3)通过将先前确定的最小毒力决定因素纳入与禽类死亡率无关的替代WN病毒遗传骨架，评估替代WNV基因型出现的可能性。适应无毒的西尼罗河病毒基因型乌鸦也将进行调查，以衡量鸟类毒力的选择作为一种机制，出现北美西尼罗河病毒基因型。关键的基本信息的作用，病毒复制和机制，调节禽水库内的天然病毒种群的毒力，将允许更有效地实施疫苗接种计划和预测未来的西尼罗河病毒爆发。此外，病毒复制和发病机理的基础知识将为疫苗和抗病毒策略的开发提供见解。

项目成果

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

西尼罗河病毒温度敏感性和禽类毒力受到NS1-2B多态性的调节。

• 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