Cytomegalovirus retinitis pathogenesis: Mechanisms of retinal tissue destruction

 描述(申请人提供)：艾滋病相关的人类巨细胞病毒(HCMV)视网膜炎导致无法接受联合抗逆转录病毒疗法(CART)或未能坚持或对CART有反应的艾滋病毒免疫抑制患者失明和失明。因此，艾滋病相关的巨细胞病毒视网膜炎仍然是世界范围内的一个严重的眼科问题。在提高我们诊断、预防和/或治疗艾滋病相关性巨细胞病毒视网膜炎的能力方面取得进展的一个关键障碍是缺乏对巨细胞病毒这种人类疱疹病毒在艾滋病相关性巨细胞病毒视网膜炎发生和发展过程中导致视网膜组织破坏的机制的了解。我们的目标是通过获得所需的信息来解决艾滋病相关性HCMV视网膜炎的问题和进展的关键障碍，以确定细胞因子信号转导抑制因子1(SOCS1)、SOCS3、坏死性下垂和下垂在艾滋病相关性HCMV视网膜炎发病机制中的相对作用。我们的中心假设是SOCS1、SOCS3、坏死性上睑下垂和下垂分别通过不同的机制共同作用于艾滋病相关性HCMV视网膜炎的视网膜组织破坏。我们的目标是使用一种成熟的临床相关的小鼠巨细胞病毒(MCMV)视网膜炎动物模型，在逆转录病毒诱导的免疫抑制(MAIDs)小鼠中结合体外细胞培养方法来(1)获得所需的信息，以了解SOCS1、SOCS3、坏死症和软下垂在MAIDs相关的MCMV视网膜炎演变过程中促进视网膜组织破坏的机制，以及(2)使用这些信息来证明这些视网膜组织破坏机制也在艾滋病相关的MCMV视网膜炎中起作用。这些目标将通过三个特定目标的成功完成来实现：(1)检验SOCS1和SOCS3蛋白在MAIDER相关MCMV视网膜炎的发病机制中起重要作用的假设，(2)检验坏死性下垂和下垂在MAIDER相关性MCMV视网膜炎发病机制中起重要作用的假说，以及(3)检验在艾滋病相关的HCMV视网膜炎中，HCMV刺激SOCS1、SOCS3、坏死性下垂和下垂的假说。我们的预期结果将包括：(1)巨细胞病毒通过眼内刺激SOCS1和SOCS3蛋白促进视网膜组织破坏，这些蛋白干扰JAK/STAT通路和/或Toll样受体(TLR)信号以抑制抗病毒I型干扰素的产生；(2)巨细胞病毒通过眼内刺激多条细胞死亡途径促进视网膜组织破坏，包括坏死性下垂和细胞凋亡；(3)巨细胞病毒通过SOCS1、SOCS3、坏死性下垂和下垂机制促进艾滋病相关性巨细胞病毒视网膜炎期间视网膜组织的破坏。对艾滋病相关的巨细胞病毒视网膜炎研究领域的影响将包括可能直接或间接导致治疗艾滋病相关的巨细胞病毒视网膜炎以及其他源于疱疹病毒的视网膜疾病的新的治疗方法的新信息。

 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.