TRIM Interactions with Arthritic Alphaviruses

TRIM 与关节炎甲病毒的相互作用

基本信息

批准号：
8249185
负责人：
Mark T Heise
金额：
$ 21.89万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249185
关键词：
Acute Affect Alphavirus Antiviral Agents Arthritis Biological Assay Bypass Cells Chikungunya virus Complex Development Disease Family member Fibroblasts HIV Human IFN consensus sequence binding protein Immune response Immune system In Vitro Infection Inflammation Inflammatory Response Inflammatory Response Pathway Interferons Joints Lead Light Mediating Mus Myositis PML gene Pathogenesis Play Rheumatoid Arthritis Role Ross river virus Signal Pathway Sindbis Virus Small Interfering RNA Staging Structural Protein System TRIM Motif Testing Therapeutic Intervention Venezuelan Equine Encephalitis Virus Viral Viral Structural Proteins Virus Virus Diseases Virus Replication base human TRIM25 protein in vivo interest macrophage mouse model novel therapeutic intervention overexpression pathogen research study viral RNA virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Arthritic alphaviruses, such as Chikungunya virus (CHIKV) and Ross River virus (RRV) cause severe acute and persistent arthritis and myositis in infected humans and are significant emerging disease threats. A growing body of evidence suggests that CHIKV and related viruses have a complex interplay with the host innate immune response, where the type I IFN system is required for control of viral replication, but an overactive host inflammatory response contributes to virus-induced disease. Therefore, in order to develop new therapeutic approaches for these important human pathogens, it is essential that we have a better understanding of how these pathogens interact with the innate immune system. Tripartite motif- containing (TRIM) family members are key players in the host innate immune system, where TRIMs can act as antiviral effector molecules, modulate the type I IFN induction/signaling pathway, or regulate the host inflammatory response. We were interested in determining whether TRIM family members contribute to the control or exacerbation of alphavirus-induced inflammatory arthritis and found that several TRIM family members, including TRIM21 and TRIM34 were significantly upregulated in the joints of mice suffering from either RRV or CHIKV- induced arthritis. Furthermore, a combination of over expression assays and siRNA mediated knockdown studies indicate that both TRIM21 and TRIM34 have antiviral activity against CHIKV and RRV, but not against two other alphaviruses, Sindbis virus and Venezuelan equine encephalitis virus (VEEV), suggesting that TRIM21 and TRIM34 specifically interact with a subset of related alphaviruses. Based on these preliminary results, we propose to utilize a combination of in vitro and in vivo approaches to investigate the mechanism(s) by which TRIM21 and TRIM34 inhibit CHIKV/RRV replication and assessTRIM21's role in regulating the CHIKV induced inflammatory response in a mouse model of CHIKV-induced arthritis. These studies will elucidate the mechanisms underlying the anti-alphavirus activities of TRIM21 and TRIM34, shed new light on the mechanisms regulating alphavirus-induced arthritis, and may ultimately lead to the development of new therapies aimed at inhibiting the replication of CHIKV and related viruses or modulating the virus-induced inflammatory response. Relevance: Arthritic alphaviruses such as chikungunya virus (CHIKV) and Ross River virus (RRV) are significant emerging disease threats, yet we know relatively little about how these viruses induce disease or how the host innate immune response controls their spread. The proposed studies, which will evaluate the role of tripartite motif-containing (TRIM) family members in controlling CHIKV and RRV replication and the virus-induced inflammatory response, have the potential to expand our understanding of how arthritic alphaviruses interact with the host innate immune system and may identify new targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Arthritic alphaviruses such as chikungunya virus (CHIKV) and Ross River virus (RRV) are significant emerging disease threats, yet we know relatively little about how these viruses induce disease or how the host innate immune response controls their spread. The proposed studies, which will evaluate the role of tripartite motif- containing (TRIM) family members in controlling CHIKV and RRV replication and the virus-induced inflammatory response, have the potential to expand our understanding of how arthritic alphaviruses interact with the host innate immune system and may identify new targets for therapeutic intervention

描述（由申请人提供）：关节炎α病毒，例如Chikungunya病毒（Chikv）和Ross River病毒（RRV），导致受感染人类的严重急性和持续性关节炎和肌炎，并且是重大的新兴疾病威胁。越来越多的证据表明，CHIKV和相关病毒与宿主先天免疫反应具有复杂的相互作用，其中I型IFN系统需要控制病毒复制，但是过度活跃的宿主炎症反应导致病毒诱导的疾病。因此，为了为这些重要的人类病原体开发新的治疗方法，我们必须更好地了解这些病原体如何与先天免疫系统相互作用。含有三方基序（TRIM）家族成员是宿主先天免疫系统的关键参与者，在该系统中，Trims可以充当抗病毒效应分子，调节I型IFN诱导/信号传导途径或调节宿主炎症反应。我们有兴趣确定修剪家庭成员是否有助于控制或加剧α病毒引起的炎症性关节炎，并发现在患有RRV或Chikv-刺激的关节的小鼠关节中，包括TRIM21和TRIM34在内的几个Trim家族成员显着上调。此外，过度表达测定和siRNA介导的敲低研究的组合表明，TRIM21和TRIM34都具有针对Chikv和RRV的抗病毒活性，但对其他两种α病毒，Sindbis病毒和委内瑞拉委内瑞拉脑炎病毒（VEEV）的抗病毒活性，暗示了Trim21和Trim21和Trim34的相互作用。基于这些初步结果，我们建议利用体外和体内方法的组合来研究TRIM21和TRIM34抑制CHIKV/RRV复制和评估Trim21在调节CHIKV诱导的CHIKV诱导的CHIKV诱导的ARTHRISIT炎症的炎症反应中的作用的机制。这些研究将阐明TRIM21和TRIM34抗α24抗α34的抗α34的机制，并为调节α病毒诱导的关节炎的机制提供了新的启示，并可能最终导致旨在抑制Chikv及相关病毒或调节病毒或调节病毒性诱导的新疗法的开发。相关性：关节炎α病毒，例如基孔肯雅病毒（Chikv）和罗斯河病毒（RRV）是重大的新兴疾病威胁，但我们对这些病毒如何诱导疾病或宿主先天免疫反应如何控制其传播相对较少了解。提出的研究将评估三方基序（TRIM）家族成员在控制CHIKV和RRV复制中的作用以及病毒诱导的炎症反应，具有扩展我们对关节炎α病毒与宿主先天免疫系统如何相互作用的理解，并可能确定治疗干预的新目标。公共卫生相关性：关节炎α病毒（例如Chikungunya病毒（Chikv）和Ross River病毒（RRV）是重大的新兴疾病威胁，但我们对这些病毒如何诱导疾病或宿主的先天免疫反应如何控制其传播相对较少了解。提出的研究将评估含三方基序（TRIM）家族成员在控制CHIKV和RRV复制中的作用以及病毒引起的炎症反应，具有扩展我们对关节炎α病毒如何与宿主先天免疫系统相互作用的理解的潜力