THE VIROME AND ADVERSE OUTCOMES IN LUNG TRANSPLANTATION

摘要 肺移植是众多终末期肺病患者的首选治疗方法 失败了。不幸的是，肺移植后5年的长期结果仍然令人失望。 存活率只有50%，大大落后于其他固体器官移植。最常见的两种 肺移植后早期可能发生的易导致晚期移植失败的事件为缺血。 再灌注损伤导致的原发移植物功能障碍(PGD)和急性排斥反应(AR)。PGD最多发生在 25%的肺移植受者，并导致死亡率增加。超过一半的患者会发生AR，并且 导致慢性排斥反应的风险增加。虽然目前的教条清楚地表明，天生的和适应性的 免疫反应在PGD和AR的病因中起着重要作用，但几乎没有努力去研究 确定病毒在PGD中的潜在作用，几乎没有公正的、系统的努力来评估 病毒与AR的关系。对于肺移植受者，肺内持续或潜伏的病毒，如 以及在血液中系统循环的病毒，可能会重新感染肺部，可能会影响 肺移植的结果。下一代测序(NGS)的出现使第一个 对给定的病毒体(即完整的病毒谱)进行时间、系统和公正的分析 生物标本。至关重要的是，界定病毒及其与疾病的潜在联系的努力 肺移植的背景严重缺乏。R61阶段的目标是前瞻性地收集 来自肺移植受者队列的样本，并确定病毒与 PGD和/或AR。R33阶段的目标是在独立队列中验证R61的结果， 通过建立细胞培养和小鼠来鉴定与PGD和/或AR相关的病毒 最后，确定小鼠肺移植模型中病毒感染对PGD和/或AR的影响。

ABSTRACT Lung transplantation is the therapy of choice for numerous patients suffering from end stage pulmonary failure. Unfortunately, long term outcomes after lung transplantation remain disappointing with 5-year graft survival rates of only 50%, which lag substantially behind other solid organ transplants. The two most common events that can occur early after lung transplantation and that predispose to late graft failure are ischemia reperfusion injury-mediated primary graft dysfunction (PGD) and acute rejection (AR). PGD occurs in up to 25% of lung transplant recipients and leads to enhanced mortality. AR occurs in more than half of patients and leads to increased risk of chronic rejection. While current dogma clearly suggests that innate and adaptive immune responses play significant roles in the etiologies of PGD and AR, there has been almost no effort to define a potential role of viruses in PGD, and there have been few unbiased, systematic efforts to evaluate viral associations with AR. For lung transplant recipients, persistent or latent viruses within the lung itself, as well as viruses systemically circulating in the blood that could infect the lung de novo, could potentially impact outcomes in lung transplantation. The advent of Next Generation Sequencing (NGS) has enabled for the first time, systematic and unbiased analysis of the virome (i.e. the complete spectrum of viruses) of a given biological specimen. Critically, efforts to define the virome, and its potential association with disease in the context of lung transplantation are sorely lacking. The goals of the R61 Phase are to prospectively collect specimens from a cohort of lung transplant recipients and define statistical associations of the virome with PGD and or AR. The goals of the R33 phase are to validate results from the R61 in an independent cohort, characterize the viruses that are associated with PGD and/or AR by establishing cell culture and mouse models, and finally to define the impact of viral infection in a mouse lung transplant model on PGD and/or AR.