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: 8188056
• 负责人: CHARLES H COOK
• 金额: $ 30.2万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188056
• 关键词: Address; American; Animal Model; Antibodies; Antiviral Agents; Attention; Caring; Clinical Data; Clinical Trials; Complication; Country; Critical Illness; Cytomegalovirus; Cytomegalovirus Infections; Diagnostic; Funding; Herpesviridae; Hospitals; Human; Immune; Immune response; Immunocompetent; Immunoglobulin G; Infection; Infection Control; Inflammatory Response; Injury; Intensive Care Units; Knowledge; Lung; Lung diseases; Memory; Methods; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Outcome; Patients; Peptides; Population; Prevention strategy; Retirement; Risk; School-Age Population; Sepsis; Serum; Stress; T memory cell; Testing; Therapeutic; Time; Tissues; Translating; Transplant Recipients; Ventilator; Viral Load result; Virus; Virus Diseases; Work; adaptive immunity; clinically relevant; density; experience; improved; in vivo; insight; lung injury; mortality; novel; novel strategies; pathogen; patient population; preconditioning; prevent; prospective; reactivation from latency

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. PUBLIC HEALTH RELEVANCE: CMV infects ~50-60% of Americans by school age and up 80-90% by retirement. CMV is not cleared, but becomes dormant after primary infection, periodically reactivating during times of stress or immune compromise. CMV reactivation is a difficult complication in transplant patients that until recently has received little attention in immune competent patients. We (and others) have recently observed that many previously healthy patients with latent CMV experience unrecognized reactivation of this virus during critically illness or injury. This is associated with lung disease and prolonged ventilator durations. Previously healthy patients with CMV reactivation also have roughly double the risk of dying (55% versus 30%) in the hospital than patients without reactivation. Millions of patients are hospitalized each year in intensive care units throughout the country, and ~ 1 in 3 at risk will reactivate this virus during their illness.

描述（由申请人提供）：巨细胞病毒（CMV）是感染大多数人类的普遍存在的病原体。与其他疱疹病毒一样，这些感染得到控制，但并未完全根除。残留在多个组织中的休眠病毒可以在压力或免疫受损时重新激活。我们和许多其他人已经认识到，约 33% 免疫功能正常的患者在危重疾病期间肺部会发生 CMV 再激活。 CMV 是免疫抑制患者中公认的病原体，并且越来越多地被认为是重症免疫功能正常患者中的潜在病原体。最近的临床数据表明，CMV 再激活与这些患者的发病率和死亡率恶化相关，促使开展抗病毒治疗的前瞻性临床试验 (1U01HL102547)。我们的首要假设是，潜伏的 CMV 感染及其免疫反应对该患者群体具有致病潜力。由于人类研究的局限性，我们开发了 CMV 潜伏/重新激活的小鼠模型。使用该模型，我们已经证实脓毒症引发的 CMV 重新激活可导致免疫功能正常宿主的肺损伤，这一发现支持了现有的临床数据。尽管取得了这些重大进展，但我们的理解仍然存在三个主要差距：1）CMV 如何使免疫能力强的宿主容易遭受肺损伤，2）我们能否识别那些最有 CMV 相关损伤风险的人，以及 3）CMV 相关风险是否可以改善在免疫能力强的宿主中？在本提案中，我们将使用我们的动物模型来解决每个具体问题。在目标 1 中，我们将研究免疫活性宿主 CMV 重新激活期间肺损伤的机制。我们将检验以下假设：巨细胞病毒感染使宿主产生由细菌性败血症释放的免疫病理学免疫潜力。在目标 2 中，我们将研究现有方法的新应用，以确定重新激活和不良结果的风险。我们将测试 CMV IgG 滴度可预测病毒载量和 CMV 相关风险的新假设。在目标 3 中，我们将测试两种高度新颖的方法来防止 CMV 重新激活。我们将测试以下假设：在先前感染的宿主中，CMV 相关风险可以得到缓解。这些研究代表了我们之前工作的直接延续，我们期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，从而改善对危重患者的护理。 公共卫生相关性：CMV 在学龄期感染约 50-60% 的美国人，到退休时感染率高达 80-90%。 CMV 不会被清除，但在初次感染后会进入休眠状态，在压力或免疫受损时定期重新激活。 CMV 再激活是移植患者的一种困难并发症，直到最近在免疫功能正常的患者中还很少受到关注。我们（和其他人）最近观察到，许多以前健康的患有潜伏巨细胞病毒的患者在危重疾病或受伤期间经历了这种病毒未被识别的重新激活。这与肺部疾病和呼吸机持续时间延长有关。先前健康的 CMV 重新激活患者在医院死亡的风险也比未重新激活的患者大约高一倍（55% 与 30%）。全国每年有数百万患者在重症监护室住院，大约三分之一的患者在患病期间会重新激活这种病毒。