Infections in Hematopoietic Cell Transplant Recipients

 描述(由申请人提供)：以患者为中心的造血细胞移植(HCT)感染研究提供了直接影响HCT接受者结局的机会。感染仍然是HCT后发病和死亡的主要原因。这一奖项续展将为申请者提供受保护的时间来指导受训人员进行临床研究，这些研究直接与了解HCT后感染的生物学有关。结果将为将其转化为改进的管理策略提供依据。这项提案将针对移植传染病的四个领域：呼吸道病毒感染、感染遗传学、微生物组和人类疱疹病毒6型(HHV-6)疾病的表现。研究目的：1.探讨临床、宿主和病毒因素对人鼻病毒(HRV)感染的影响。人鼻病毒是HCT术后上下呼吸道疾病的重要原因。在大型队列研究中(N=1750)，我们将确定从上呼吸道疾病进展到下呼吸道疾病(LRD)的危险因素。我们还将研究宿主反应(细胞因子、基因表达谱)在HRV患者中的作用以及与临床症状和结果(进展、死亡率)的相关性，并确定病毒载量、毒株差异和病毒脱落对疾病进展、发病率和死亡率的影响。具体目的2.确定供受者先天遗传因素对HCT术后感染并发症风险和结局的影响。使用5000名捐赠者和接受者的独特队列，我们将进行全基因组关联研究。我们将根据真菌抗原血症和临床结果定义和验证侵袭性曲霉病(IA)表型，然后定义增加IA获得风险的遗传变异。使用相同的队列，我们将定义增加重要病毒感染风险的基因变异。具体目标3.确定抗生素的使用和膳食纤维摄入量如何影响 HCT后肠道微生物区系及后续感染。在一项前瞻性队列研究中(N=500)，我们将确定抗生素方案和膳食纤维摄入对肠道微生物区系和 细菌并发症，并确定肠道微生物区系的变化是否调节了对病毒感染的易感性并影响适应性免疫。具体目标4.开展研究以确定 HHV-6作为HCT受者的肺部病原体。在一组通过支气管肺泡灌洗评估为肺炎的患者(N=725)中，我们将检测HHV-6病毒载量、病毒整合和HHV-6 LRD的细胞因子表达谱，并表征与总体死亡率和呼吸衰竭死亡相关的因素。这些目的支持在移植传染病领域对POR采取创新的方法，拟议的研究具有极大的潜力促进我们对感染并发症谱、疾病的遗传基础和微生物组的作用的了解。

 DESCRIPTION (provided by applicant): Patient-oriented research of infections in hematopoietic cell transplantation (HCT) provides the opportunity to directly affect outcome of HCT recipients. Infections continue to be a major cause of morbidity and death after HCT. This award renewal will provide protected time for the applicant to mentor trainees in clinical research that is directly related to understanding the biology of infections after HCT. Results wil provide the basis for translation into improved management strategies. This proposal will address four areas of transplant infectious diseases: respiratory virus infections, genetics of infections, the microbiome, and human herpesvirus 6 (HHV- 6) disease manifestations. The Specific Aims are: Specific Aim 1. To investigate clinical, host and viral factors affecting advers outcomes in HCT recipients with human rhinovirus (HRV) infection, which is now the significant cause of upper and lower respiratory tract disease after HCT. In large cohort study (N=1750) we will define risk factors for progression from upper to lower respiratory tract disease (LRD). We will also examine the role of host responses (cytokines, gene expression profiles) in patients with HRV and correlate with clinical symptoms and outcomes (progression, mortality), and determine the impact of viral load, strain differences and viral shedding on disease progression, morbidity, and mortality. Specific Aim 2. To determine the impact of donor and recipient innate genetic factors on the risk and outcome of infectious complications following HCT. Using a unique cohort of 5000 donor and recipients we will perform genome-wide association studies. We will define and validate invasive aspergillosis (IA) phenotypes based on fungal antigenemia and clinical outcomes, and then define genetic variants that increase risk for IA acquisition. Using the same cohort, we will define genetic variants that increase the risk of important viral infections. Specific Aim 3. To determine how the use of antibiotics and dietary fiber intake affect gut microbiota and subsequent infections after HCT. In a prospective cohort study (N=500) we will determine the effect of antibiotic regimens and dietary fiber intake on the gut microbiota and bacterial complications, and determine if changes in gut the microbiota modulate susceptibility to viral infection and affect adaptive immunity. Specific aim 4. To conduct studies to characterize HHV-6 as a pulmonary pathogen in HCT recipients. In a cohort of patients evaluated for pneumonia by bronchoalveolar lavage (N=725), we will examine HHV-6 viral load, viral integration and cytokine expression profiles of HHV-6 LRD and characterize factors associated with overall mortality and death due to respiratory failure. These aims support an innovative approach toward POR in the field of transplant infectious diseases and the proposed studies have a high potential of advancing our knowledge of the spectrum of infectious complications, the genetic basis of diseases, and the role of microbiome.