CMV Replication During Primary Infection in Lung Transplant Recipients

描述（由申请方提供）：巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者（LTR）中最常见的感染。活动性CMV感染（包括CMV肺炎）与急性排斥反应发作相关，并且通过尚不清楚的机制是慢性排斥反应（闭塞性细支气管炎综合征）的公认风险因素。供者+/受体（D+R-）-不匹配的LTR发生CMV疾病的风险最高，并显示死亡率增加。此外，活动性CMV感染的发病机制和与临床严重程度相关的因素，如肺炎仍然知之甚少。该建议的中心假设是，同种异体移植物中的病毒复制和宿主适应性T细胞反应调节CMV肺炎的发展及其临床严重程度。我们的初步数据表明，CMV病毒载量较高，在肺气道（支气管肺泡灌洗; BAL）相比，在原发性感染的血浆。因此，在SA 1中，我们将进一步验证在原发性感染期间，与血液相比，同种异体移植物中的复制增加。我们还将检验我们的假设，即与无肺炎的LTR相比，有肺炎的LTR的BAL病毒载量增加。我们还将使用我们开发的新型急性肺移植功能障碍分级系统，确定BAL病毒载量是否随临床严重程度的加重而升高。由于我们在肺炎期间检测到CMV特异性CD 8 + T细胞大量流入肺气道，我们将在SA 2中进一步确定肺炎期间宿主对CMV的CD 8+应答的幅度是否增加，以及CD 8 + T细胞应答是否与初次感染期间的BAL和/或血浆病毒载量和急性同种异体移植物功能障碍呈正相关。这些CMV特异性免疫研究已由PI根据R21奖励（R21 AI 072537 - 01 A1）在D+ R-LTR中进行。PI，John McDyer，MD，是K 08获奖者，移植肺病学家和免疫学家，他致力于了解肺移植受者CMV感染和疾病的发病机制。他为该项目组建了一个由移植感染性疾病、生物统计学和移植后肺病理学方面的共同研究者/顾问组成的专家团队。该奖项将为LTR中CMV的强大人类原发性感染模型中的新翻译工作提供基础，以解决这些临床相关问题。 公共卫生相关性：实体器官移植，包括肺移植，每年挽救许多生命。巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者中最常见的感染，与急性和慢性排斥反应的风险增加以及死亡率增加有关，但原因尚不清楚。了解CMV复制与宿主对CMV感染的免疫反应，以及易感肺移植受者的严重程度的临床指标可能会提高我们对CMV感染的检测，并可能影响所有实体器官移植受者的治疗策略和长期结局。

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Active CMV infection, including CMV pneumonitis, is associated with acute rejection episodes and is a recognized risk factor for chronic rejection (bronchiolitis obliterans syndrome) through poorly understood mechanisms. Donor+/Recipient(D+R-)- mismatched LTRs are at highest risk for CMV disease and demonstrate increased mortality. Moreover, the pathogenesis of active CMV infection and factors associated with clinical severity, such as pneumonitis remain poorly understood. The central hypothesis of this proposal is that both viral replication in the allograft and the host adaptive T cell response regulate the development of CMV pneumonitis and its clinical severity. Our preliminary data show that CMV viral load is higher in the lung airways (bronchoalveolar lavage; BAL) compared to the plasma during primary infection. Therefore, In SA1 we will further validate that replication is increased in the allograft compared to the blood during primary infection. We will also test our hypothesis that BAL viral loads are increased in LTRs with pneumonitis compared to those without. We will also determine whether BAL viral loads are higher with worse clinical severity, using a novel acute lung allograft dysfunction grading system that we have developed. Because we detect a massive influx of CMV-specific CD8+ T cells into the lung airways during pneumonitis, we will further determine in SA2 whether the magnitude of the host CD8+ response to CMV is increased during pneumonitis, and whether the CD8+ T cell response positively correlates with BAL and/or plasma viral loads and acute allograft dysfunction during primary infection. These CMV-specific immune studies are already being conducted in D+R- LTRs by the PI under an R21 award (R21 AI072537-01A1). The PI, John McDyer, MD, is a K08 awardee, transplant pulmonologist, and immunologist, who is strongly committed to understanding pathogenesis of CMV infection and disease in lung transplant recipients. He has assembled an expert team of co-investigators/consultants in transplant infectious disease, biostatistics, and post-transplant lung pathology for this project. This award will provide a foundation for novel translational work in a robust human primary infection model of CMV in LTRs to address these clinically relevant issues. PUBLIC HEALTH RELEVANCE: Solid organ transplantation, including lung transplantation, saves many lives each year. Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients, and is associated with increased risk for both acute and chronic rejection, and increased mortality, though it is unclear why. Understanding CMV replication in conjunction with the host immune response to CMV infection, and clinical measures of severity in susceptible lung transplant recipients may improve our detection of CMV infection, as well as potentially impact treatment strategies and long-term outcomes in all solid organ transplant recipients.