Mechanisms of alphavirus infectivity and adaptation - Resubmission - 1
甲病毒感染性和适应机制 - 重新提交 - 1
基本信息
- 批准号:10444392
- 负责人:
- 金额:$ 53.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
Arboviruses are transmitted from insect vectors to humans, yet the molecular mechanisms that govern this
critical step in the viral life cycle are not completely understood. Chikungunya virus (CHIKV) has undergone
several natural adaptation events, acquiring mutations in the viral glycoproteins that have increased its
infectivity and transmission, yet how the glycoproteins promote infectivity, spread, and disease in vivo is
unclear. We harnessed the power of in vivo viral evolution and identified a new evolutionary intermediate in β-
strand c of the CHIKV E1 glycoprotein that led to increased transmission in mosquitoes and increased
replication and pathogenesis in mice, indicating that these glycoprotein regions are crucial for promoting viral
infectivity and disease. Preliminary studies from our lab show that E1 β-strand c plays essential roles in virion
thermostability, fusion, and cholesterol-dependent entry. Moreover, using viral evolution we have identified
host-specific genetic interactions between CHIKV E1 and E2. Based on these preliminary studies, we
hypothesize that CHIKV E1 and E2 drive distinct mechanisms of entry into insects and mammals and that
temperature and lipid composition in mosquitoes drives viral adaptation. Our overall goal is to understand the
fundamental mechanisms by which the CHIKV structural proteins regulate alphavirus infectivity and
dissemination in insects and mammals, and to elucidate what drives the adaptation of the glycoprotein in
insects. Here, we use complementary biochemical, genetic, in vitro and in vivo approaches coupled with deep
sequencing technologies to establish how the CHIKV structural proteins function to promote entry and CHIKV
pathogenesis and transmission in vivo (Aim 1), and to establish how temperature and host lipids impact
CHIKV-vector interactions in mosquitoes (Aim 2). Understanding the discrete mechanisms of how the viral
structural proteins regulate infectivity in insects and mammals, and how host lipids impact adaptation is
essential to understanding how arboviruses are transmitted, spread, and cause disease.
项目摘要
arbovirus是从昆虫向量传播到人类的,但是控制此的分子机制
病毒生命周期中的关键步骤尚未完全理解。 Chikungunya病毒(Chikv)已经发生了
几个自然适应事件,在病毒糖蛋白中加速突变,这些突变增加了
感染性和传播,但是糖蛋白如何促进体内感染,传播和疾病是
不清楚。我们利用体内病毒进化的力量,并确定了β-中新的进化中间体
Chikv E1糖蛋白的链C导致蚊子的传播增加并增加
小鼠的复制和发病机理,表明这些糖蛋白区域对于促进病毒至关重要
感染力和疾病。我们实验室的初步研究表明,E1β链c在病毒体中起着重要的作用
热稳定性,融合和胆固醇依赖性进入。此外,使用病毒进化我们已经确定
CHIKV E1和E2之间的宿主特异性遗传相互作用。基于这些初步研究,我们
假设Chikv E1和E2推动了进入昆虫和哺乳动物的不同机制,并且
蚊子中的温度和脂质组成驱动病毒适应。我们的总体目标是了解
CHIKV结构蛋白调节α病毒感染的基本机制和
在昆虫和哺乳动物中传播,并阐明了驱动糖蛋白适应的因素
昆虫。在这里,我们使用完整的生化,遗传,体外和体内方法,加上深
测序技术以确定CHIKV结构蛋白如何促进进入和CHIKV
在体内发病机理和传播(AIM 1),并确定温度和宿主脂质如何影响
蚊子中的Chikv-Vector相互作用(AIM 2)。了解病毒的离散机制
结构性蛋白质调节昆虫和哺乳动物的感染,以及宿主脂质的影响如何适应
了解如何传播,传播和引起疾病至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
Kenneth Staplefor...的其他基金
Mechanisms of alphavirus infectivity and adaptation - Resubmission - 1
甲病毒感染性和适应机制 - 重新提交 - 1
- 批准号:1055642410556424
- 财政年份:2022
- 资助金额:$ 53.24万$ 53.24万
- 项目类别:
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Mechanisms of alphavirus infectivity and adaptation - Resubmission - 1
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- 批准号:1055642410556424
- 财政年份:2022
- 资助金额:$ 53.24万$ 53.24万
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