Bacterial Sepsis & Reactivation of Laten Cytomegalovirus

细菌性败血症

• 批准号: 7052827
• 负责人: CHARLES H COOK
• 金额: $ 28.52万
• 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/7052827
• 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）具有原发性感染后潜在的能力。 CMV以后可以从潜伏期中重新激活，并且后面的重新激活是免疫抑制的移植和AIDS患者中众所周知的病原体。我们最近证明，病重的手术患者也可以重新激活潜在的CMV，并且在这些患者中似乎是一种肺病原体，发病率恶化，可能是死亡率。不幸的是，这种重新激活的触发因素仍然未知。许多刺激与重新激活有关，包括免疫抑制，移植，细胞因子刺激和细菌败血症的同种异体刺激。使用动物模型，我们最近证明，腹腔内细菌败血症会引起免疫能力小鼠肺中潜在CMV的远距离激活。此外，我们已经表明，这种重新激活发生在多个器官中，这表明循环介质可能参与。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，已被证明是CMV复制的刺激性，因此在此模型中可能是重新激活的。此外，已知这些介体会引起严重的局部器官炎症，我们的初步数据表明，这种局部炎症可能有助于从潜伏期中重新激活CMV。最后，我们的初步数据还表明，从潜伏期中重新激活CMV也会引起免疫能力宿主的病理。因此，该建议将集中于确定细菌败血症在免疫能力宿主肺中诱导潜在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：败血症诱导的炎症介质在系统或局部起作用，刺激潜伏期的CMV重新激活。在特定目标I中，我们将评估系统性和局部炎症在潜在CMV重新激活中的作用。具体目标II将研究核因子Kappa B激活在败血症触发的重新激活中的作用。在特定的目标III中，我们将进一步研究肺CMV重新激活的损害作用。我们实验室的长期目标是阐明重症患者中延迟的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。