Cytomegalovirus retinitis pathogenesis: Mechanisms of retinal tissue destruction

 描述（由申请人提供）：艾滋病相关的人巨细胞病毒（HCMV）视网膜炎导致无法获得联合抗逆转录病毒治疗（cART）或未能坚持或响应cART的HIV免疫抑制患者的视力丧失和失明。因此，艾滋病相关的HCMV视网膜炎仍然是世界范围内的一个重要眼科问题。在提高我们诊断、预防和/或治疗AIDS相关的HCMV视网膜炎的能力方面进展的关键障碍是缺乏对HCMV（一种人疱疹病毒）在AIDS相关的HCMV视网膜炎的发作和进展期间引起视网膜组织破坏的机制的理解。我们的目标是解决艾滋病相关的HCMV视网膜炎的问题，并通过获得所需的信息，以建立细胞因子信号转导抑制因子1（SOCS 1），SOCS 3，坏死性凋亡和焦亡在艾滋病相关的HCMV视网膜炎的发病机制的相对作用进展的关键障碍。我们的中心假设是，SOCS 1，SOCS 3，坏死性凋亡，焦亡个别合谋通过不同的机制，共同促进视网膜组织破坏在艾滋病相关的HCMV视网膜炎的发病机制。我们的目的是使用一个完善的和临床相关的小鼠巨细胞病毒（MCMV）视网膜炎的动物模型，在小鼠中进行逆转录病毒诱导的免疫抑制（MAIDS），并结合体外细胞培养方法，以（1）获得所需的信息，以了解SOCS 1，SOCS 3，坏死性凋亡和焦亡在MAIDS相关MCMV视网膜炎演变过程中导致视网膜组织破坏的机制，和（2）使用这些信息来证明这些视网膜组织破坏机制在AIDS相关的HCMV视网膜炎中也起作用。这些目标将通过成功完成三个具体目标来实现：（1）检验SOCS 1和SOCS 3蛋白在MAIDS相关MCMV视网膜炎的发病机制中起重要作用的假设，（2）检验坏死性凋亡和焦亡在MAIDS相关MCMV视网膜炎的发病机制中起重要作用的假设，和（3）检验HCMV刺激SOCS 1、SOCS 3、坏死性凋亡，以及艾滋病相关HCMV视网膜炎中的焦亡。我们的预期结果将包括确定（1）MCMV通过眼内刺激SOCS 1和SOCS 3蛋白促进视网膜组织破坏，SOCS 1和SOCS 3蛋白干扰JAK/STAT通路和/或toll样受体（TLR）信号传导，抑制抗病毒I型干扰素（IFN）的产生，（二）MCMV通过眼内刺激多种细胞死亡途径（包括坏死性凋亡和焦亡）促进视网膜组织破坏（3）HCMV通过SOCS 1、SOCS 3、坏死性凋亡和焦亡机制在AIDS相关HCMV视网膜炎期间促进视网膜组织破坏。对艾滋病相关HCMV视网膜炎研究领域的影响将包括新的信息，这些信息可能直接或间接导致新的治疗方法，用于管理艾滋病相关HCMV视网膜炎以及其他疱疹病毒起源的视网膜疾病。

 DESCRIPTION (provided by applicant): AIDS-related human cytomegalovirus (HCMV) retinitis causes vision loss and blindness in HIV-immuno- suppressed patients who do not have access to combination antiretroviral therapy (cART) or who fail to adhere to or respond to cART. AIDS-related HCMV retinitis therefore remains a significant ophthalmologic problem worldwide. A critical barrier to progress in advancing our ability to diagnose, prevent, and/or treat AIDS- related HCMV retinitis is an absence of an understanding of the mechanisms by which HCMV, a human  herpesvirus, causes retinal tissue destruction during onset and progression of AIDS-related HCMV retinitis. Our goal is to address the problem of AIDS-related HCMV retinitis and the critical barrier to progress by obtaining the information needed to establish the relative role of suppressor of cytokine signaling 1 (SOCS1), SOCS3, necroptosis, and pyroptosis in the pathogenesis of AIDS-related HCMV retinitis. Our central hypothesis is that SOCS1, SOCS3, necroptosis, and pyroptosis individually conspire via different mechanisms to contribute collectively to retinal tissue destruction during the pathogenesis of AIDS-related HCMV retinitis. Our objectives are to use a well-established and clinically relevant animal model of mouse cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS) coupled with in vitro cell culture approaches to (1) obtain the information needed to understand the mechanisms by which SOCS1, SOCS3, necroptosis, and pyroptosis contribute to retinal tissue destruction during evolution of MAIDS-related MCMV retinitis, and (2) use this information to demonstrate that these mechanisms of retinal tissue destruction also operate during AIDS-related HCMV retinitis. These objectives will be met through successful completion of three Specific Aims: (1) test the hypothesis that SOCS1 and SOCS3 proteins play a significant role in the pathogenesis of MAIDS-related MCMV retinitis, (2) test the hypothesis that necroptosis and pyroptosis play a significant role in the pathogenesis of MAIDS-related MCMV retinitis, and (3) test the hypothesis that HCMV stimulates SOCS1, SOCS3, necroptosis, and pyroptosis during AIDS-related HCMV retinitis. Our expected outcomes will include establishing that (1) MCMV promotes retinal tissue destruction through intraocular stimulation of SOCS1 and SOCS3 proteins that interfere with the JAK/STAT pathway and/or toll-like receptor (TLR) signaling to dampen antiviral Type I  interferon (IFN) production, (2) MCMV promotes retinal tissue destruction through intraocular stimulation of multiple cell death pathways that include necroptosis and pyroptosis as well as apoptosis, and (3) HCMV promotes retinal tissue destruction during AIDS-related HCMV retinitis via SOCS1, SOCS3, necroptosis, and pyroptosis mechanisms. The impact on the field of AIDS-related HCMV retinitis research will include new information that could directly or indirectly lead to novel therapeutic approaches for management of AIDS-related HCMV retinitis as well as other retinal diseases of herpesvirus origin.