Viral and immune kinetics in rhinovirus infection following hematopoietic cell transplantation

项目摘要 人鼻病毒是上、下呼吸道最常见的呼吸道病毒 在造血细胞移植（HCT）受者中; HRV下呼吸道感染后的死亡率 与已知的肺部病毒病原体相似，包括呼吸道合胞病毒，流感， 和副流感病毒。尽管高疾病负担和观察到的HRV感染并发症 在HCT接受者中，HRV治疗的发展受到缺乏全面的 了解病毒检测、症状和宿主免疫反应之间的关系， 这些因素对疾病严重程度的影响。我们已经证明，临床风险因素，包括 血细胞减少和类固醇使用与上呼吸道感染（URTI）进展相关， LRTI。然而，高达70%的患者在病毒感染时存在严重的免疫抑制， 他们的感染得不到治疗我们的初步数据表明，在基因表达的签名时， URTI可能预示着进展为LRTI。我们的目标是描述病毒检测， HCT受者HRV感染早期细胞因子水平和细胞免疫应答的前瞻性研究 监测队列。我们还将在单细胞水平上进行深入的基因表达分析， 与外周血和近端淋巴细胞中严重疾病相关的特定细胞群 支气管肺泡灌洗液。该建议的中心假设是病毒和宿主免疫动力学， 包括特定组织区室中的整体和细胞特异性基因表达谱， HRV感染的HCT受者的严重程度。这些实验的结果将表征最佳的 时间和最具预测性的病毒和宿主免疫标志物，可用于设计合理的临床试验， 新疗法。我们对区室和细胞特异性免疫反应的深入研究将进一步促进我们的免疫学研究。 了解病毒与宿主的相互作用和潜在的干预目标。

PROJECT SUMMARY Human rhinovirus (HRV) is the most common respiratory virus detected in the upper and lower respiratory tract in hematopoietic cell transplant (HCT) recipients; mortality rates following HRV lower respiratory tract infection are similar to those seen with known pulmonary viral pathogens including respiratory syncytial virus, influenza, and parainfluenza virus. Despite the high burden of disease and the observed complications of HRV infection in HCT recipients, the development of HRV therapeutics is hindered by the lack of a comprehensive understanding of the relationship between viral detection, symptoms and host immune responses and the impact of these factors on disease severity. We have demonstrated that clinical risk factors, including cytopenias and steroid use, are associated with progression from upper respiratory tract infection (URTI) to LRTI. However, up to 70% of patients with profound immunosuppression at the time of virus acquisition clear their infections without treatment. Our preliminary data show that gene expression signatures at the time of URTI may be predictive of progression to LRTI. We aim to characterize the interplay between viral detection, cytokine levels and cellular immune responses early during HRV infection in HCT recipients in a prospective surveillance cohort. We will also perform in depth gene expression analyses at a single cell level to identify specific cellular populations that are associated with severe disease in both peripheral blood and in proximal bronchoalveolar lavage fluid. The central hypothesis of this proposal is that viral and host immune kinetics, including both global and cell specific gene expression profiles in specific tissue compartments, impact disease severity in HCT recipients with HRV infection. Results from these experiments will characterize the optimal timing and most predictive viral and host immune markers that can be used to design rational clinical trials for novel therapeutics. Our deep interrogation of compartment and cell specific immune responses will further our understanding of virus-host interactions and of potential targets for intervention.