VIROLOGIC & IMMUNOLOGIC STUDIES OF MURINE CMV RETINITIS

病毒学

• 批准号: 2162808
• 负责人: SALLY S ATHERTON
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2162808
• 关键词: T lymphocyte; artificial immunosuppression; biomarker; cytomegalovirus; disease /disorder model; host organism interaction; laboratory mouse; latent virus infection; passive immunization; regulatory gene; retinitis; virus replication

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection observed in patients with AIDS, and development of CMV retinitis depends on immunodeficiency. In normal, non-immunosuppressed individuals, CMV is usually latent, and if the virus does reactivate, presumably the virus-infected cells are quickly eliminated by the host's immune system. In contrast, in the immunosuppressed host, such as patients with AIDS or those patients who are systemically immunocompromised following an organ transplant, a bone marrow transplant, or during chemotherapy, CMV can cause disseminated disease with both systemic and ocular manifestations. The inability of the host to mount an effective immune response to the virus likely contributes much to the pathogenesis of this disease by allowing the virus to replicate, and both systemic and local infections with CMV are associated with immunosuppression. During the first funding period, we demonstrated that inoculation of 5 x 10/2 PFU of MCMV into immunosuppressed BALB/c mice (steroid-treated or T cell depleted) resulted in fulminant retinal necrosis in the majority (>90%) of the mice. Virus became latent at several sites, including the eye, and could be reactivated by immunosuppression. During latency, a majority of the latently-infected eyes were positive for transcripts of the MCMV immediate early gene 1 (IE1). The murine model of MCMV retinitis will be used in the studies proposed in this application to: (1) determine whether immunosuppression-induced reactivation of latent MCMV in the eye results from in situ reactivation of ocular virus, from hematogenous spread of reactivated virus from extraocular sites, or from a combination of in situ reactivation and hematogenous dissemination of reactivated virus, (2) determine whether production of IE1 mRNA is a marker for MCMV latency in the eye, and (3) determine whether adoptive transfer of NK cells, macrophages, and/or virus-specific T cells protects against MCMV retinitis following supraciliary inoculation. Results from studies to identify sites of MCMV latency and to use a cellular approach to prevent MCMV retinitis may help us understand the pathogenic mechanisms of CMV retinitis in human patients. Results of experiments to see whether IE1 transcripts are markers of MCMV latency in the mouse eye may ultimately be useful for predicting which CMV-seropositive, HIV-1 infected patients are at the highest risk of developing CMV retinitis.

巨细胞病毒视网膜炎是最常见的眼部机会性眼病 观察艾滋病患者的感染和巨细胞病毒视网膜炎的发展 取决于免疫缺陷。在正常的、非免疫抑制的个体中， CMV通常是潜伏的，如果病毒确实重新激活，推测 被病毒感染的细胞会被宿主的免疫系统迅速清除。 相反，在免疫抑制的宿主中，如艾滋病患者或 那些器官后全身免疫功能受损的患者 移植，骨髓移植，或在化疗期间，CMV可以 导致具有全身和眼部症状的播散性疾病。 宿主不能对病毒产生有效的免疫反应 病毒可能在这种疾病的发病机制中起了很大作用 允许病毒复制，以及全身和局部感染 巨细胞病毒感染与免疫抑制有关。在第一次资助期间 期间，我们证明了将5×10/2pfu的MCMV接种到 免疫抑制的BALB/c小鼠(类固醇治疗或T细胞耗尽) 在大多数(90%)小鼠中出现暴发性视网膜坏死。病毒 在几个部位潜伏，包括眼睛，并可能 被免疫抑制重新激活。在延迟期间，大多数 潜伏感染的眼睛对即时MCMV转录本呈阳性 早期基因1(IE1)。MCMV视网膜炎的小鼠模型将用于 本申请中提出的研究目的是：(1)确定 免疫抑制导致眼部潜伏的MCMV重新激活 从眼部病毒的原位再激活，从血源性传播 从眼外部位或从原位的组合重新激活的病毒 再激活病毒的再激活和血液传播，(2) 确定IE1mRNA的产生是否是MCMV潜伏期的标志 以及(3)确定NK细胞的过继转移是否， 巨噬细胞和/或病毒特异性T细胞对MCMV视网膜炎的保护作用 在进行睫状上接种之后。来自研究的结果以确定 MCMV潜伏期的部位并使用细胞方法来预防MCMV 视网膜炎可能有助于我们了解巨细胞病毒的致病机制 人类患者的视网膜炎。实验结果，看看IE1是否 转录本是小鼠眼睛中MCMV潜伏期的标志，最终可能是 有助于预测哪些CMV血清阳性、HIV-1感染的患者 罹患巨细胞病毒性视网膜炎的风险最高。