Genetic determinants of adaptation of two flaviviruses

两种黄病毒适应的遗传决定因素

• 批准号: 8481500
• 负责人: Laura D Kramer
• 金额: $ 34.64万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481500
• 关键词: Accounting; Address; Arboviruses; Birds; Cells; Comparative Study; Consensus; Coupled; Culicidae; Disease; Disease Outbreaks; Elements; Environment; Epidemiology; Evaluation; Evolution; Exhibits; Flaviviridae; Flavivirus; Generations; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Variation; Genotype; Habitats; Health; Heterogeneity; In Vitro; Individual; Knowledge; Laboratories; Laboratory Study; Minority; Mutation; Natural regeneration; North America; Pattern; Polymerase; Population; Procedures; Relative (related person); Research; Role; Shapes; St. Louis Encephalitis Virus; Ticks; Tissues; United States; Variant; Viral; Virus; West Nile virus; base; fitness; in vivo; mutant; novel; pathogen; pressure; research study; success; transmission process

DESCRIPTION (provided by applicant): The emergence and rapid biogeographic expansion of West Nile Virus (WNV; Flaviviridae; Flavivirus) throughout the western hemisphere, as well as the re-emergence of other medically significant viruses, highlight the vulnerability of the United States to both novel and reemerging viral pathogens. To understand how zoonotic viruses evolve following introduction to new habitats, it is necessary to address the selective pressures shaping viral adaptation. Specifically, we must characterize factors important in determining the plasticity (ability of individual genotypes to generalize to many hosts) and adaptability (ability to rapidly produce fitter genotypes) of virus populations interacting with different hosts in order to evaluate the capacity for geographic expansion into new environments. The mechanisms that account for success of a virus in colonization of new environments are poorly characterized. Experimental studies in naturally relevant hosts are generally lacking in virus adaptation studies. These studies are required to provide plausible and relevant mechanistic explanations for adaptability. The proposed research will address this fundamental gap in the state of knowledge through laboratory studies using natural and ecologically relevant mosquito and avian hosts. Studies in the laboratory are the best way to conduct a systematic evaluation of the factors that influence viral adaptation. We have chosen to undertake a comparative study with two flaviviruses, WNV and St. Louis encephalitis virus (SLEV). These two viruses are very closely related antigenically, genetically, and structurally. Nevertheless, their epidemiological patterns in the western hemisphere have differed strongly in recent years. WNV has continued to expand both its host and geographic ranges, producing significant levels of disease in the U.S. every year since its emergence. SLEV, on the other hand, exhibits only periodic outbreaks which remain relatively contained. Whether WNV activity in North America will ultimately mimic that of SLEV remains to be seen, but a comparative study of current genotypes should elucidate genetic correlates which define variable epidemiological patterns. Recent experimental studies in our laboratory have revealed apparent differences in in vitro adaptation between SLEV and WNV. Our extensive BSL-3 laboratory, insectary, and vivarium will allow us to confirm and expand the in vitro results in vivo in natural hosts and further characterize important factors that both constrain and facilitate arbovirus activity in disparate hosts and new environments. These are among the first studies, to the best of our knowledge, using natural vertebrate and mosquito hosts to elucidate mechanisms of viral adaptation.

描述（由申请人提供）：西尼罗河病毒（WNV; Flaviviridae; Flavivivirus）的出现和生物地理扩张遍布整个西半球，以及其他具有医学上重要的病毒的重新启动，突出了美国对新颖和重新组成的病毒病原体的脆弱性。为了了解新栖息地引入新栖息地之后的人畜共患病如何发展，有必要解决塑造病毒适应的选择性压力。具体而言，我们必须表征对确定可塑性（单个基因型推广到许多宿主的能力）和适应性（能够快速产生较合适的基因型的能力）与不同宿主相互作用的病毒的能力（能力），以评估地理扩展到新环境的能力。解释病毒在新环境定植中成功的机制的特征很差。在病毒适应研究中通常缺乏自然相关宿主的实验研究。这些研究需要为适应性提供合理且相关的机械解释。拟议的研究将使用自然和生态相关的蚊子和禽宿主通过实验室研究来解决知识状态的这一基本差距。实验室的研究是对影响病毒适应因素进行系统评估的最佳方法。我们选择与两种黄病毒（WNV）和圣路易斯脑炎病毒（SLEV）进行比较研究。这两种病毒在抗原，遗传和结构上密切相关。然而，近年来，他们的流行病学模式在西半球方面有很大差异。 WNV一直在扩大其宿主和地理范围，自出现以来，每年在美国产生大量的疾病。另一方面，SLEV仅表现出相对包含的周期性暴发。北美的WNV活性是否最终会模仿SLEV的活性尚待观察，但是对当前基因型的比较研究应阐明遗传相关性，从而定义了可变流行病学模式。在我们实验室中的最新实验研究表明，SLEV和WNV之间体外适应的明显差异。我们广泛的BSL-3实验室，昆虫和体内的实验室将使我们能够在天然宿主中确认和扩展体内的体内结果，并进一步表征重要因素，这些因素既约束宿主和新环境中的Arbovirus活性。据我们所知，这些研究是使用自然脊椎动物和蚊子宿主来阐明病毒适应机制的最早研究。

项目成果

Dispersal of Culex mosquitoes (Diptera: Culicidae) from a wastewater treatment facility.

• DOI: 10.1603/me11077
• 发表时间: 2012-01
• 期刊: Journal of medical entomology
• 影响因子: 2.1
• 作者: Ciota AT;Drummond CL;Ruby MA;Drobnack J;Ebel GD;Kramer LD
• 通讯作者: Kramer LD

Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes.

• DOI: 10.1371/journal.ppat.1005009
• 发表时间: 2015-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Van Slyke GA;Arnold JJ;Lugo AJ;Griesemer SB;Moustafa IM;Kramer LD;Cameron CE;Ciota AT
• 通讯作者: Ciota AT

Exposure to West Nile Virus Increases Bacterial Diversity and Immune Gene Expression in Culex pipiens.

接触西尼罗河病毒会增加淡色库蚊的细菌多样性和免疫基因表达。

• DOI: 10.3390/v7102886
• 发表时间: 2015
• 期刊: Viruses
• 作者: Zink,StevenD;VanSlyke,GretaA;Palumbo,MichaelJ;Kramer,LauraD;Ciota,AlexanderT
• 通讯作者: Ciota,AlexanderT

Experimental passage of St. Louis encephalitis virus in vivo in mosquitoes and chickens reveals evolutionarily significant virus characteristics.

• DOI: 10.1371/journal.pone.0007876
• 发表时间: 2009-11-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ciota AT;Jia Y;Payne AF;Jerzak G;Davis LJ;Young DS;Ehrbar D;Kramer LD
• 通讯作者: Kramer LD

Temporal and spatial alterations in mutant swarm size of St. Louis encephalitis virus in mosquito hosts.

蚊子宿主中圣路易斯脑炎病毒突变群大小的时间和空间变化。

• DOI: 10.1016/j.meegid.2010.12.007
• 发表时间: 2011
• 期刊: Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases
• 作者: Ciota,AlexanderT;Koch,EvanM;Willsey,GrahamG;Davis,LaurenJ;Jerzak,GretaVS;Ehrbar,DylanJ;Wilke,ClausO;Kramer,LauraD
• 通讯作者: Kramer,LauraD