CMV Replication During Primary Infection in Lung Transplant Recipients

描述（由申请人提供）：巨细胞病毒（CMV）是实体器官移植受者中最常见的感染，尤其是肺移植受者（lts）。活动性巨细胞病毒感染，包括巨细胞病毒肺炎，与急性排斥反应发作有关，并且是慢性排斥反应（闭塞性细支气管炎综合征）的公认危险因素，其机制尚不清楚。供体+/受体（D+R-）不匹配的LTRs发生巨细胞病毒疾病的风险最高，死亡率增加。此外，活动性巨细胞病毒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细胞反应调节巨细胞病毒肺炎的发展及其临床严重程度。我们的初步数据显示，与原发性感染时的血浆相比，肺气道（支气管肺泡灌洗；BAL）中的巨细胞病毒载量更高。因此，在SA1中，我们将进一步验证在初次感染期间，与血液相比，同种异体移植物中的复制增加。我们还将验证我们的假设，即与没有肺炎的ltr相比，患有肺炎的ltr中BAL病毒载量增加。我们还将使用我们开发的一种新型急性同种异体肺功能障碍分级系统，确定BAL病毒载量是否更高，临床严重程度是否更差。由于我们在肺炎期间检测到CMV特异性CD8+ T细胞大量流入肺气道，我们将在SA2中进一步确定宿主CD8+对CMV的反应强度是否在肺炎期间增加，以及CD8+ T细胞反应是否与原发性感染期间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特异性免疫研究已经由PI根据R21奖（R21 AI072537-01A1）在D+R- lts中进行。首席研究员John McDyer，医学博士，是K08奖获得者，移植肺科专家和免疫学家，他坚定地致力于了解肺移植受者巨细胞病毒感染和疾病的发病机制。他为这个项目组建了一个由移植传染病、生物统计学和移植后肺病理学专家组成的联合调查/顾问团队。该奖项将为在ltr中建立强大的CMV人类原发感染模型的新型转化工作提供基础，以解决这些临床相关问题。

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.