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/文摘

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.