TRIM Interactions with Arthritic Alphaviruses

描述（由申请人提供）：关节炎甲病毒，例如基孔肯雅病毒（CHIKV）和罗斯河病毒（RRV），会在感染者中引起严重的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应答具有复杂的相互作用，其中I型IFN系统是控制病毒复制所必需的，但过度活跃的宿主炎症应答有助于病毒诱导的疾病。因此，为了开发针对这些重要的人类病原体的新治疗方法，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。含有三分基序（TRIM）的家族成员是宿主先天免疫系统中的关键参与者，其中TRIM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。我们感兴趣的是确定TRIM家族成员是否有助于甲病毒诱导的炎性关节炎的控制或恶化，并发现几种TRIM家族成员，包括TRIM 21和TRIM 34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，过表达测定和siRNA介导的敲低研究的组合表明，TRIM 21和TRIM 34都具有针对CHIKV和RRV的抗病毒活性，但不具有针对另外两种甲病毒辛德毕斯病毒和委内瑞拉马脑炎病毒（VEEV）的抗病毒活性，这表明TRIM 21和TRIM 34与相关甲病毒的子集特异性相互作用。基于这些初步结果，我们提出利用体外和体内方法的组合来研究TRIM 21和TRIM 34抑制CHIKV/RRV复制的机制，并在CHIKV诱导的关节炎的小鼠模型中评估TRIM 21在调节CHIKV诱导的炎症反应中的作用。这些研究将阐明TRIM 21和TRIM 34的抗甲病毒活性的机制，为调节甲病毒诱导的关节炎的机制提供新的线索，并可能最终导致开发旨在抑制CHIKV和相关病毒复制或调节病毒诱导的炎症反应的新疗法。 相关性：关节炎甲病毒，如基孔肯雅病毒（CHIKV）和罗斯河病毒（RRV）是重要的新兴疾病威胁，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知之甚少。拟议的研究将评估含三重基序（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病毒如何与宿主先天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：关节炎甲病毒，如基孔肯雅病毒（CHIKV）和罗斯河病毒（RRV）是重要的新兴疾病威胁，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知之甚少。拟议的研究将评估含三重基序（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病毒如何与宿主先天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