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.

项目概要/摘要 该职业发展奖将有助于补充风险基础病毒学研究的知识和技能 第 4 组毒剂，需要在最高防护实验室 (BSL-4) 中处理。这对于 目标是成为一名独立研究员，成为高致病性传染病专家。目标 颁奖期间的目的是通过体内和体外研究揭示拉沙热（LF）的新机制 技术，从而对对抗措施和控制方法的发展产生新的见解 拉沙热。 拉沙病毒（LASV）在西非国家流行，每年都会引起拉沙病毒的爆发。虽然LASV 从公共卫生角度来看，它是最令人担忧的病原体之一，但有效的疫苗或药物很少 针对 LF 的治疗。由于 LASV 具有高致病性，必须按照生物安全 4 级 (BSL-4) 进行处理。这 是开发 LF 预防或治疗方法的最大障碍之一。此外， LF动物模型有限，这对于基础研究和对策开发至关重要。 最近，我们开发了一种新型LF豚鼠模型，发现LASV毒株LF2384和LF2350具有 豚鼠的致病表型完全不同。这两种病毒已从人类体内分离出来 LF患者和豚鼠中这些病毒的致病性与人类病例一致。这些独特的 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 揭示导致 LASV 致病性的病毒因素和潜在的分子机制。在 在拟议的研究中，我们将确定导致 LASV 致病性的因素并揭示新的分子 通过使用反向遗传学、体内实验和一些体外实验研究 LASV 感染的机制 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，我们将揭示以下疾病的病理生理学： 豚鼠 LASV 感染。在具体目标 2 中，我们将确定导致 LASV 的病毒因素 通过使用反向遗传学和体内研究确定致病性。在具体目标 3 中，我们将揭示分子机制 LASV 的潜在致病性。总之，我们希望解决 LASV 的新致病机制 感染，从而产生针对 LF 制定对策的新见解。

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.