TRIM Interactions with Arthritic Alphaviruses

描述(申请人提供)：关节炎甲型病毒，如基孔肯雅病毒(CHIKV)和罗斯河病毒(RRV)，会在感染的人类中引起严重的急性和持续性关节炎和肌炎，是新出现的重大疾病威胁。越来越多的证据表明，CHIKV和相关病毒与宿主的先天性免疫反应有复杂的相互作用，其中I型干扰素系统是控制病毒复制所必需的，但过度活跃的宿主炎症反应导致了病毒诱导的疾病。因此，为了开发针对这些重要人类病原体的新的治疗方法，我们必须更好地了解这些病原体是如何与天然免疫系统相互作用的。含有三个基序的TRIM家族成员是宿主先天免疫系统中的关键成员，TRIM可作为抗病毒效应分子，调节I型干扰素诱导/信号通路，或调节宿主的炎症反应。我们有兴趣确定TRIM家族成员是否有助于控制或加重甲型病毒诱导的炎症性关节炎，并发现包括TRIM21和TRIM34在内的几个TRIM家族成员在患有RRV或CHIKV诱导的关节炎的小鼠的关节中显著上调。此外，过表达分析和siRNA介导的敲除研究相结合表明，TRIM21和TRIM34对CHIKV和RRV都有抗病毒活性，但对另外两种甲病毒Sindbis病毒和委内瑞拉马脑炎病毒(VEEV)没有抗病毒活性，这表明TRIM21和TRIM34与相关的甲病毒亚群具有特异性相互作用。基于这些初步结果，我们建议采用体外和体内相结合的方法来研究TRIM21和TRIM34抑制CHIKV/RRV复制的机制(S)，并评价TRIM21‘S在CHIKV诱导的关节炎小鼠模型中调节CHIKV诱导的炎症反应中的作用。这些研究将阐明TRIM21和TRIM34的抗甲病毒活性的机制，为甲病毒诱导的关节炎的调控机制提供新的线索，并最终可能导致旨在抑制CHIKV和相关病毒的复制或调节病毒诱导的炎症反应的新疗法的开发。相关性：基孔肯雅病毒(CHIKV)和罗斯河病毒(RRV)等关节炎甲型病毒是新出现的重大疾病威胁，但我们对这些病毒如何致病或宿主先天免疫反应如何控制其传播知之甚少。这些研究将评估含三方基序(TRIM)家族成员在控制CHIKV和RRV复制以及病毒诱导的炎症反应中的作用，有可能扩大我们对关节炎甲型病毒如何与宿主先天性免疫系统相互作用的理解，并可能确定治疗干预的新靶点。 公共卫生相关性：基孔肯雅病毒(CHIKV)和罗斯河病毒(RRV)等关节炎甲型病毒是新出现的重大疾病威胁，但我们对这些病毒如何致病或宿主先天免疫反应如何控制其传播知之甚少。这些拟议的研究将评估含有三个基序的家族成员在控制CHIKV和RRV复制以及病毒诱导的炎症反应中的作用，有可能扩大我们对关节炎甲型病毒如何与宿主先天性免疫系统相互作用的理解，并可能确定治疗干预的新靶点。

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