Viral factors responsible for Lassa virus pathogenicity

拉沙病毒致病性的病毒因素

• 批准号: 10462688
• 负责人: Junki Maruyama
• 金额: $ 6.32万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2023-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462688
• 关键词: Acute; Address; Africa; African; Animal Model; Annual Reports; Arenavirus; Arenavirus Infections; Award; Basic Science; Biological; Biological Containment; Blood; Case Fatality Rates; Cavia; Clinical; Clinical Chemistry; Clinical Data; Communicable Diseases; Containment; Country; Data; Development; Disease; Disease Outbreaks; Family member; Functional disorder; Glycoproteins; Goals; Gold; Guinea; Hematology; Hemorrhage; Histopathology; Human; Immune Evasion; Immune response; Immunocompetent; Immunologics; In Vitro; Infection; K-Series Research Career Programs; Knowledge; Laboratories; Lassa Fever; Lassa virus; Liberia; Methods; Modeling; Molecular; Molecular Biology; Nigeria; Nucleoproteins; Pathogenesis; Pathogenicity; Pathologic; Patients; Persons; Phenotype; Preventive; Public Health; Recombinants; Research; Research Personnel; Risk; Rodent Model; Safety; Sensorineural Hearing Loss; Sierra Leone; System; Techniques; Therapeutic; Vaccines; Viral; Viral Pathogenesis; Viral Proteins; Virulence; Virulence Factors; Virus; Virus Diseases; base; cost; experimental study; guinea pig model; improved; in vivo; in vivo Model; insight; nonhuman primate; novel; pathogen; pathogenic virus; research and development; reverse genetics; skills; tool

PROJECT SUMMARY/ABSTRACT This career development award will help fill in the knowledge and skills in basic virological research of Risk Group 4 agents, which need to be handled in the highest containment laboratory (BSL-4). This is essential for the goal to become an independent researcher as an expert on highly pathogenic infectious diseases. The goal during the award period is to reveal novel mechanisms of Lassa fever (LF) by using both in vivo and in vitro techniques, leading to new insight into the development of countermeasures and controlling methods against Lassa fever. Lassa virus (LASV) is endemic in West African countries and causes outbreaks of LF annually. Although LASV is one of the most alarming pathogens from a public health perspective, there are few effective vaccines or therapeutics against LF. LASV must be handled at biosafety level 4 (BSL-4), due to its high pathogenicity. This is one of the largest barriers to the development of preventive or therapeutic approaches against LF. Furthermore, animal models of LF are limited, which is essential for basic research and development of countermeasures. Recently, we developed a novel guinea pig model of LF and found that LASV strain LF2384 and LF2350 have completely different pathogenic phenotypes in guinea pigs. These two viruses have been isolated from human LF patients and pathogenicity of these viruses in guinea pigs is consistent with human cases. These unique combinations of immunocompetent rodent model and clinical isolated LASVs are strong tools, which allow us to reveal viral factors responsible for pathogenicity and molecular mechanisms underlying LASV pathogenicity. In the proposed study, we will determine factors responsible for LASV pathogenicity and reveal novel molecular mechanisms underlying LASV infection by using reverse genetics, in vivo experiments, and several in vitro molecular techniques. We will address this goal through three specific aims. In Specific Aim 1, we will reveal the pathophysiology of LASV infection in guinea pigs. In Specific Aim 2, we will determine viral factors responsible for LASV pathogenicity by using reverse genetics and in vivo study. In Specific Aim 3, we will unveil molecular mechanisms underlying LASV pathogenicity. Taken together, we hope to address novel pathogenic mechanisms of LASV infection, leading to new insights to develop countermeasures against LF.

项目总结/摘要 这个职业发展奖将有助于填补风险的基础病毒学研究的知识和技能 第4组制剂，需要在最高级别的隔离实验室（BSL-4）中处理。这对于 目标是成为高致病性传染病专家的独立研究人员。目标 在获奖期间，通过使用体内和体外方法揭示拉沙热（LF）的新机制 技术，导致新的洞察发展的对策和控制方法， 拉沙热。 拉沙病毒（LASV）是西非国家的地方病，每年导致LF暴发。虽然LASV 从公共卫生的角度来看，它是最令人担忧的病原体之一，几乎没有有效的疫苗， 治疗LF。由于LASV的高致病性，必须在生物安全级别4（BSL-4）下处理。这 是发展LF预防或治疗方法的最大障碍之一。此外，委员会认为， LF的动物模型有限，这对于基础研究和对策的开发是必要的。 最近，我们建立了一种新的LF豚鼠模型，并发现LASV株LF 2384和LF 2350具有 完全不同的致病表型。这两种病毒已从人体中分离出来 LF患者和这些病毒在豚鼠中的致病性与人类病例一致。这些独特 免疫活性啮齿动物模型和临床分离的LASV的组合是强有力的工具，使我们能够 揭示了负责致病性的病毒因子和LASV致病性的分子机制。在 通过这项研究，我们将确定LASV致病性的因素，并揭示新的分子生物学机制。 通过使用反向遗传学、体内实验和几种体外实验， 分子技术 我们将通过三个具体目标来实现这一目标。在具体目标1中，我们将揭示 豚鼠中的LASV感染。在具体目标2中，我们将确定导致LASV的病毒因子 通过反向遗传学和体内试验研究其致病性。在具体目标3中，我们将揭示分子机制 潜在的LASV致病性。总之，我们希望解决LASV的新的致病机制 感染，导致新的见解，以制定针对LF的对策。

项目成果

Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses.

• DOI: 10.1073/pnas.2206104119
• 发表时间: 2022-09-06
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

• DOI: 10.1038/s41598-022-19780-7
• 发表时间: 2022-09-15
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Cao, Xia;Maruyama, Junki;Zhou, Heyue;Fu, Yanwen;Kerwin, Lisa;Powers, Colin;Sattler, Rachel A.;Manning, John T.;Singh, Alok;Lim, Reyna;Healy, Laura D.;Johnson, Sachi;Cabral, Elizabeth Paz;Li, Donghui;Lu, Lucy;Ledesma, Arthur;Lee, Daniel;Richards, Susan;Rivero-Nava, Laura;Li, Yan;Shen, Weiqun;Stegman, Karen;Blair, Benjamin;Urata, Shinji;Kishimoto-Urata, Magumi;Ko, Jamie;Du, Na;Morais, Kyndal;Lawrence, Kate;Rivera, Ianne;Pai, Chin-, I;Bresson, Damien;Brunswick, Mark;Zhang, Yanliang;Ji, Henry;Paessler, Slobodan;Allen, Robert D.
• 通讯作者: Allen, Robert D.