Bacterial Sepsis and Reactivation of Latent Cytomegalovirus

细菌性败血症和潜伏巨细胞病毒的再激活

• 批准号: 8841520
• 负责人: CHARLES H COOK
• 金额: $ 17.14万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-02 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841520
• 关键词: Bacterial; Sepsis; Reactivation; Latent; Cytomegalovirus

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is a ubiquitous pathogen infecting most humans. Like other herpes viruses, these infections are controlled but not completely eradicated. Dormant virus remaining in multiple tissues can reactivate during times of stress or immune compromise. We and numerous others have recognized that CMV reactivation occurs in lungs of ~33% of immune competent patients during critical illness. CMV is an accepted pathogen in immune suppressed patients that is increasingly being recognized as a potential pathogen in critically ill immune competent patients. Recent clinical data have associated CMV reactivation with worsened morbidity and mortality in these patients, prompting a prospective clinical trial with antiviral treatment (1U01HL102547). It is our overarching hypothesis that latent CMV infection and the immune responses to it have pathogenic potential for this patient population. Because of limitations in human studies, we have developed a murine model of CMV latency/reactivation. Using this model, we have confirmed that CMV reactivation triggered by sepsis can cause lung injury in immunocompetent hosts, a finding that supports available clinical data. Despite these significant advances, three major gaps remain in our understanding: 1) How does CMV predispose immune competent hosts to lung injury, 2) Can we identify those most at risk for CMV related injury, and 3) Can CMV-related risk be ameliorated in immune competent hosts? In this proposal we will address each of these specific questions using our animal model. In Aim 1 we will study mechanisms of lung injury during CMV reactivation in immunocompetent hosts. We will test the hypothesis that CMV infection preconditions the host to develop an immunopathologic immune potential that is unleashed by bacterial sepsis. In Aim 2 we will study a new application of available methods to determine risk for reactivation and poor outcome. We will test the novel hypothesis that CMV IgG titers will predict viral load and CMV-related risk. In Aim 3 we will test two highly novel approaches to prevent CMV reactivation. We will test the hypothesis that CMV-related risk can be mitigated in previously infected hosts. These studies represent a direct continuation of our previous work, and we expect that knowledge gained from this proposal will continue to translate directly into diagnostic and therapeutic strategies that will improve care for critically ill patients.

描述（由申请人提供）：巨细胞病毒（CMV）是一种无处不在的病原体，可感染大多数人类。像其他疱疹病毒一样，这些感染也受到控制，但没有完全消除。在压力或免疫损害时，保留在多个组织中的休眠病毒可以重新激活。我们和其他许多人都认识到，在肺部约33％的肺中发生了CMV重新激活。 CMV是免疫抑制患者的一种公认的病原体，越来越多地被认为是严重不良免疫能力的患者的潜在病原体。最近的临床数据已将CMV重新激活与这些患者的发病率和死亡率恶化有关，从而促使对抗病毒治疗进行了前瞻性临床试验（1U01HL102547）。我们的总体假设是，潜在的CMV感染及其对该患者人群具有致病潜力。由于人类研究的局限性，我们开发了CMV潜伏/重新激活的鼠模型。使用此模型，我们已经证实，由败血症触发的CMV重新激活可能会导致免疫能力宿主的肺损伤，这一发现支持可用的临床数据。尽管取得了重大进展，但我们的理解仍然存在三个主要差距：1）CMV易于免疫受到肺部损伤的诱因，2）我们是否可以确定与CMV相关损伤最有风险的人，3）3）与CMV相关的风险能否在免疫胜任的宿主中得到改善？在此提案中，我们将使用我们的动物模型解决这些特定问题。在AIM 1中，我们将研究免疫能力宿主CMV重新激活期间肺损伤的机制。我们将检验以下假设：CMV感染前提是宿主开发细菌败血症释放的免疫病理免疫潜力。在AIM 2中，我们将研究可用方法的新应用，以确定重新激活和结果不佳的风险。我们将测试CMV IgG滴度将预测病毒载荷和与CMV相关的风险的新假设。在AIM 3中，我们将测试两种高度新颖的方法，以防止CMV重新激活。我们将检验以下假设：在先前感染的宿主中可以减轻与CMV相关的风险。这些研究代表了我们以前的工作的直接延续，我们希望从该提案中获得的知识将继续直接转化为诊断和治疗策略，以改善对重症患者的护理。