SFTSV nonstructural protein NSs-mediated immunopathogenesis

SFTSV 非结构蛋白 NSs 介导的免疫发病机制

• 批准号: 10162492
• 负责人: Jae U Jung
• 金额: $ 60.42万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162492
• 关键词: 2 year old; 4 year old; Age; Animal Model; Animals; Anti-Inflammatory Agents; Antiviral Agents; Autophagosome; Characteristics; China; Clinical; Code; Complex; Country; Dangerousness; Disease; Family; Far East; Fatality rate; Ferrets; Fever; Genes; Genome; Genus Phlebovirus; Host Defense; Human; Immune; Immune Evasion; Immunosuppression; In Vitro; Inclusion Bodies; Infection; Interferon Type I; Interferons; Interleukin-10; Leukocytes; Lipids; MAP3K8 gene; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Nonstructural Protein; Nucleoproteins; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Production; Protein Kinase; RNA; Recombinants; Reporting; Risk Factors; Role; Severe Fever with Thrombocytopenia Syndrome Virus; Signal Pathway; Signal Transduction; Source; Symptoms; TBK1 gene; TRIM25 gene; Therapeutic; Thrombocytopenia; Ticks; Time; Treatment Efficacy; Vaccines; Viral; Viral Pathogenesis; Virus; Virus Diseases; World Health Organization; age related; aged; base; clinical Diagnosis; cytokine; in vivo; kinase inhibitor; mortality; mouse model; mutant; neutralizing antibody; novel; pathogen; protein kinase inhibitor; response; reverse genetics; transmission process; young adult

Project Summary/Abstract Severe fever with thrombocytopenia syndrome virus (SFTSV) listed in the World Health Organization 9 most dangerous pathogens is an emerging Phlebovirus in the Phenuiviridae family. Due to the lack of therapy and vaccine against SFTSV infection, there is a pressing need to understand the pathogenesis of SFTSV to develop effective antiviral agents. Designated as Biosafety level 3 agent, SFTSV contains a genome comprised of three segments of negative or ambisense RNA designated as large, medium, and small. The S segment encodes a nucleoprotein and a nonstructural protein (NSs) via an ambisense coding strategy. (Aim 1) We have discovered that NSs targets the Vps15-Vps34 lipid kinase complex to form virus-induced autophagosome-like inclusion bodies (IB), subsequently sequestrating IFN signaling effectors (RIG-I, TRIM25, and TBK1) to the IB and thereby suppressing IFN production. (Aim 2) We have also found that SFTSV NSs plays an essential role in viral immunopathogenesis by targeting the TPL2-ABIN2-p105 kinase complex to robustly induce expression of immune suppressive genes, specifically IL-10 cytokine. (Aim 3) We combined viral reverse genetics, a TPL2 kinase inhibitor, Tpl2-/- and il10-/- mouse models to show that the NSs-mediated activation of TPL2 signaling pathway robustly induced IL-10 production that was essential for viral pathogenesis. For the first time, we developed an age- dependent ferret model: young adult ferrets (<2 years old) did not show any clinical symptoms and mortality; however, SFTSV-infected aged ferrets (>4 years old) demonstrated severe thrombocytopenia, reduced white blood cells, and high fever with ~90% mortality rate, fully recapitulating human clinical manifestation. With well-established in vitro experimental conditions and novel in vivo animal models, the proposed study not only demonstrates the critical role of SFTSV NSs in viral immune evasion and pathogenesis, but also identifies potential therapeutic approaches to treat SFTSV-infected patients.

项目总结/文摘