Bacterial Sepsis & Reactivation of Latent Cytomegaloviru

细菌性败血症

• 批准号: 6610118
• 负责人: CHARLES H COOK
• 金额: $ 29.21万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-08 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610118
• 关键词: Herpesviridae disease; biological signal transduction; cytomegalovirus; enzyme linked immunosorbent assay; gel mobility shift assay; host organism interaction; immunocytochemistry; immunodeficiency; immunopathology; inflammation; interleukin 8; laboratory mouse; latent virus infection; lung; nuclear factor kappa beta; polymerase chain reaction; pulmonary fibrosis /granuloma; septicemia; toll like receptor; tumor necrosis factor alpha; virus infection mechanism

DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV), like other beta herpes viruses, has the ability to become latent following primary infection. CMV can later reactivate from latency, and following reactivation is a well known pathogen in immmunosuppressed transplant and AIDS patients. We have recently demonstrated that critically ill surgical patients can also reactivate latent CMV, and that it appears to be a pulmonary pathogen in these patients, with worsened morbidity and possibly mortality. Unfortunately, the trigger for this reactivation remains unknown. A number of stimuli have been related to reactivation, including immunosuppression, allogeneic stimulation from transplant, cytokine stimulation, and bacterial sepsis. Using an animal model, we have recently demonstrated that intra-abdominal bacterial sepsis can cause distant reactivation of latent CMV in lungs of immunocompetent mice. Further, we have shown that this reactivation occurs in multiple organs, suggesting the possible involvement of a circulating mediator. Several inflammatory mediators released during sepsis, including endotoxin and tumor necrosis factor, have been shown to be stimulatory to CMV replication, and thus might be responsible for reactivation in this model. In addition, these mediators are known to cause significant local end organ inflammation, and our preliminary data suggests that this local inflammation may contribute to reactivation of CMV from latency. Finally, our preliminary data also suggests that reactivation of CMV from latency also causes pathology in the immunocompetent host. This proposal, therefore, will focus on determining the mechanisms by which bacterial sepsis induces reactivation of latent CMV in lungs of immunocompetent hosts. Based upon our preliminary data, we will test the hypothesis that inflammatory mediators induced by sepsis, acting either systemically or locally, stimulate CMV reactivation from latency. In Specific Aim I, we will evaluate the role of systemic and local inflammation in reactivation of latent CMV. Specific Aim II will investigate the role of nuclear factor kappa B activation in sepsis-triggered reactivation. In Specific Aim III, we will further investigate the injurious effects of pulmonary CMV reactivation. The long-term goals of our laboratory are to elucidate the critical cellular and molecular factors mediating CMV reactivation from latency in critically ill surgical patients, and to utilize these data in directing therapy to ameliorate CMV disease.

描述（由申请人提供）： 与其他 β 疱疹病毒一样，人类巨细胞病毒 (CMV) 能够在初次感染后潜伏。 CMV 随后可以从潜伏期重新激活，并且重新激活后是免疫抑制移植和艾滋病患者中众所周知的病原体。我们最近证明，危重手术患者也可以重新激活潜伏的巨细胞病毒，并且它似乎是这些患者的肺部病原体，导致发病率和死亡率恶化。不幸的是，这种重新激活的触发因素仍然未知。许多刺激与再激活有关，包括免疫抑制、移植的同种异体刺激、细胞因子刺激和细菌性败血症。我们最近使用动物模型证明，腹内细菌性脓毒症可导致免疫活性小鼠肺部潜在巨细胞病毒的远程再激活。此外，我们已经表明这种重新激活发生在多个器官中，表明循环介质可能参与其中。败血症期间释放的几种炎症介质，包括内毒素和肿瘤坏死因子，已被证明可以刺激 CMV 复制，因此可能是该模型中 CMV 重新激活的原因。此外，已知这些介质会引起显着的局部终末器官炎症，我们的初步数据表明，这种局部炎症可能有助于巨细胞病毒从潜伏期重新激活。最后，我们的初步数据还表明，巨细胞病毒从潜伏期重新激活也会导致免疫功能正常的宿主出现病变。因此，该提案将重点确定细菌性败血症诱导免疫活性宿主肺部潜伏 CMV 重新激活的机制。根据我们的初步数据，我们将检验以下假设：脓毒症诱导的炎症介质在全身或局部发挥作用，刺激 CMV 从潜伏期重新激活。在具体目标 I 中，我们将评估全身和局部炎症在潜伏 CMV 重新激活中的作用。具体目标 II 将研究核因子 kappa B 激活在脓毒症触发的再激活中的作用。在具体目标 III 中，我们将进一步研究肺 CMV 重新激活的有害影响。我们实验室的长期目标是阐明介导重症外科患者潜伏期 CMV 重新激活的关键细胞和分子因素，并利用这些数据指导治疗以改善 CMV 疾病。