Development of a novel BSL2 system for high-throughput analysis of hantavirus entry glycoproteins

开发用于汉坦病毒侵入糖蛋白高通量分析的新型 BSL2 系统

• 批准号: 10598454
• 负责人: Rohit K Jangra
• 金额: $ 16.2万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598454
• 关键词: Address; Americas; Biology; Cardiopulmonary; Case Fatality Rates; Containment; Development; FDA approved; Glycoproteins; Hantavirus; Hantavirus Infections; Hemorrhagic Fever with Renal Syndrome; Human; Immune response; Immunology; Mediating; Molecular; Pathologic Processes; Persons; Plasmids; Public Health; Research; Rodent; Role; South American; Surface; Syndrome; System; Vaccines; Virion; Virus; genetic analysis; high throughput analysis; novel; reverse genetics; transmission process

Hantaviruses are the causative agents of hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) in Americas and Eurasia, respectively. These viruses are usually transmitted from their rodent reservoirs to human. However, multiple incidents of person-to-person transmission of a South American Andes hantavirus raises significant public health concern about these deadly viruses with up to 40% case fatality rates. No FDA-approved hantavirus vaccines and therapies exist. Cellular entry and infection of hantaviruses is mediated by its virion surface Gn/Gc glycoproteins, which are also the main target of protective immune responses. However, our understanding of the molecular determinants of Gn/Gc in hantavirus entry and antigenicity remains limited, at least partly, due to the general requirement of Biosafety level-3 (BSL3) containment for hantavirus research and the lack of a reverse genetics system. To address these limitations, multiple BSL2 pseudovirus systems have been developed. However, current BSL2 systems are limited by poor scalability and limited diversity of the generated viruses due to their inefficient plasmid-based rescue, which makes them incompatible with a more comprehensive analysis of the biology and function of the entry glycoproteins. Here, we propose to fix this major shortcoming of the hantavirus field by developing a novel BSL2 system that allows comprehensive reverse as well as forward genetic analysis of Gn/Gc’s role in virus entry and antigenicity.

汉坦病毒分别是汉塔病毒心肺综合征（HCP）和肾脏综合征（HFRS）的严重药物，分别是美洲和欧亚大陆。这些病毒通常是从啮齿动物的储层传播到人类的。但是，南美安第斯山脉汉塔病毒的人与人传播的多次事件引起了对这些致命病毒的重大关注，最高为40％的病例死亡率。没有FDA批准的汉塔病毒疫苗和疗法。汉坦病毒的细胞进入和感染是由其病毒体表面GN/GC糖蛋白介导的，这也是受保护的免疫调查的主要靶标。但是，我们对汉坦病毒进入和抗原性中GN/GC的分子决定剂的理解至少部分是由于对汉塔病毒研究的一般要求（BSL3）遏制的一般要求，并且缺乏反向遗传学系统。为了解决这些局限性，已经开发了多个BSL2假病毒系统。但是，当前的BSL2系统受到较差的可扩展性和由于其基于质粒效率低下的救援而产生的病毒多样性的有限多样性的限制，这使得它们与进入糖蛋白的生物学和功能的更全面分析不相容。在这里，我们建议通过开发一种新型的BSL2系统来解决汉坦病毒场的重大缺点，该系统允许对GN/GC在病毒进入和抗原性中的作用进行全面的逆转和正向遗传分析。