Identification of genetic determinants that condition flaviviral host specificity

鉴定调节黄病毒宿主特异性的遗传决定因素

• 批准号: 9230339
• 负责人: Bradley J Blitvich
• 金额: $ 38万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230339
• 关键词: Address; Adoption; Arthropods; Attenuated; Biological Assay; Cells; Chickens; Chimera organism; Code; Complementary DNA; Culex (Genus); Culicidae; Data; Elements; Evolution; Flavivirus; Generations; Genes; Genetic; Genetic Determinism; Genome; Goals; Health; Human; In Vitro; Individual; Infection; Insecta; Intervention; Invertebrates; Investigation; Japanese Encephalitis; Kinetics; Knowledge; Maps; Measures; Phenotype; Process; Program Development; Proteins; RNA replication; Ribosomal Frameshifting; Role; Specificity; Structural Genes; System; Testing; Tropism; Vaccination; Vaccine Design; Vaccines; Vertebrates; Viral; Virus; West Nile virus; attenuation; biological systems; design; fitness; genetic element; in vitro Assay; in vivo; insight; invertebrate host; novel; pressure; public health relevance; recombinant virus; tissue tropism; transmission process; vaccine candidate; virus genetics; virus tropism

 DESCRIPTION (provided by applicant): Most flaviviruses are transmitted horizontally between vertebrate hosts and hematophagous arthropods; thus, these viruses are exposed to fitness constraints imposed by disparate biological systems that preclude specific adaptation to either host. In contrast, other recently described flaviviruses, such as Culex flavivirus (CxFV), have no known vertebrate host and are considered to be insect-specific. Others, such as Modoc virus (MODV), are vertebrate-specific. Viruses in the latter two groups have the potential for host-specific adaptation independent of the need to maintain a compromised fitness level in each host in order to maximize their overall fitness. The evolutionary processes and underlying genetic basis for the differential host ranges and transmission cycles of these viruses have yet to be addressed; however, the presence of both dual-host (vertebrate-mosquito) and single-host (mosquito-specific and vertebrate-specific) flaviviruses makes this an optimal system for addressing some of these evolutionary constraints and the resulting genetic determinants that modulate host specificity. Thus, the overall goal of this application is to identify the genetic elements that have conditioned the differential host-ranges, transmissibility's and tropisms of dual-host and single-host Flaviviruses. Three specific aims have been designed to achieve this goal. In specific aim 1, the genetic elements that modulate the differential host ranges of dual-host and insect-specific flaviviruses will be identified by assessing the in vitro and in vivo vertebrate and mosquito infection phenotypes of chimeric viruses created between WNV and CxFV. In specific aim 2, the genetic determinants that modulate flavivirus host range will be further defined by characterizing the in vitro and in vivo replication phenotypes of viral chimeras created between a dual-host and vertebrate- specific flavivirus (WNV and MODV, respectively). In specific aim 3, two recently discovered ribosomal frameshift proteins - one uniquely encoded by all known insect-specific flaviviruses and the other by WNV and all other Japanese encephalitis serogroup viruses - will be investigated in order to determine their significance in flavivirus host adaptation.

 描述（由适用提供）：大多数黄素病毒在脊椎动物宿主和血管性节肢动物之间水平传播；因此，这些病毒暴露于不同的生物系统施加的适应性约束，这些系统排除了对任何宿主的特定适应性。相比之下，最近描述的其他黄病毒（例如Culex Flavivirus（CXFV））没有已知的脊椎动物宿主，被认为是无效的特异性宿主。其他，例如Modoc病毒（MODV），是脊椎动物特异性的。后两组中的病毒具有特定于宿主特异性适应性的潜力，独立于维持每个宿主中的适应水平受损的需求，以最大程度地提高其整体适应性。这些病毒差异宿主范围和传播周期的进化过程和基本遗传基础尚未得到解决。然而，双宿主（脊椎动物 - 摩斯奎特）和单宿主（蚊子特异性和脊椎动物特异性）黄病毒的存在使得这是解决这些进化约束的最佳系统，以及由此产生的遗传确定器调节宿主特异性。这是该应用程序的总体目标是确定遗传因素，这些遗传因素可以调节双宿主和单宿主黄病毒的差异宿主范围，传播和向型。已经设计了三个具体目标来实现这一目标。在特定的目标1中，通过评估WNV和CXFV之间产生的嵌合病毒的体外和体外脊椎动物和蚊子感染表型，可以通过评估体外和体内脊椎动物和蚊子感染表型来确定调节双宿主和昆虫特异性黄病毒的差异宿主范围的遗传因素。在特定的目标2中，通过表征病毒嵌合体的体外和体内复制表型来进一步定义调节黄病毒宿主范围的遗传决定剂。 在双宿主和脊椎动物特定的黄病毒（分别为WNV和MODV）之间创建。在特定的目标3中，将研究两个最近发现的核糖体框架蛋白 - 一种由所有已知的抑制特异性黄病毒编码，另一个由WNV和所有其他日本脑炎血清群病毒编码，以确定其在FLAVIVIRUS宿主适应中的重要性。