Viral and immune kinetics in rhinovirus infection following hematopoietic cell transplantation

造血细胞移植后鼻病毒感染的病毒和免疫动力学

• 批准号: 10415169
• 负责人: Alpana Amalkant Waghmare
• 金额: $ 78.17万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-04 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415169
• 关键词: Acute; Age; Allogenic; Biological Markers; Blood; Blood specimen; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Complex; Containment; Cytotoxic T-Lymphocytes; Data; Detection; Development; Disease; Enrollment; Equilibrium; Evaluation; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Home; Human; Immune; Immune response; Immunologic Markers; Immunologics; Immunophenotyping; Immunosuppression; Infection; Infection Control; Inflammatory; Intervention; Kinetics; Lower Respiratory Tract Infection; Lower respiratory tract structure; Lung; Modeling; Nose; Outcome; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Play; Population; Prevention strategy; Prognostic Marker; Progressive Disease; Prospective Studies; Prospective cohort; Respiratory Signs and Symptoms; Respiratory syncytial virus; Rhinovirus; Rhinovirus infection; Risk; Risk Factors; Role; Sampling; Severity of illness; Specimen; Steroids; Surveys; Symptoms; T-Lymphocyte; Therapeutic; Therapeutic Clinical Trial; Time; Tissues; Transplant Recipients; Upper Respiratory Infections; Upper respiratory tract; Viral; Viral Load result; Virus; Whole Blood; acute infection; base; burden of illness; clinical risk; cohort; cytokine; cytopenia; disorder control; early detection biomarkers; experimental study; handheld mobile device; hematopoietic cell transplantation; improved; influenzavirus; innovation; mathematical model; mortality; nasal swab; novel therapeutics; overexpression; parainfluenza virus; pathogenic virus; patient stratification; peripheral blood; prospective; rational design; respiratory; respiratory virus; risk stratification; self testing; single cell analysis; single-cell RNA sequencing; temporal measurement; transcriptome; transcriptome sequencing; transcriptomics; viral detection; virus host interaction

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.

项目总结 人鼻病毒(Hrv)是在上呼吸道和下呼吸道发现的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。尽管疾病负担很重，而且观察到了HRV感染的并发症 在接受HCT的患者中，HRV疗法的发展因缺乏全面的 了解病毒检测、症状和宿主免疫反应之间的关系以及 这些因素对疾病严重程度的影响。我们已经证明了临床风险因素，包括 细胞减少症和类固醇的使用与从上呼吸道感染(URTI)到 LRTI。然而，高达70%的患者在获得病毒时有严重的免疫抑制， 在没有治疗的情况下感染。我们的初步数据显示，当基因表达特征出现在 URTI可能是向LRTI进展的预测因素。我们的目标是描述病毒检测和病毒检测之间的相互作用。 血细胞移植受者HRV感染早期细胞因子水平和细胞免疫反应的前瞻性研究 监控队列。我们还将在单细胞水平上进行深入的基因表达分析，以确定 外周血和近端与严重疾病相关的特定细胞群 支气管肺泡灌洗液。这一提议的中心假设是病毒和宿主免疫动力学， 包括特定组织间隔中的全局和细胞特异性基因表达谱，影响疾病 HRV感染的HCT受者的严重程度。这些实验的结果将表征最优的 可用于设计合理的临床试验的时机和最具预测性的病毒和宿主免疫标志物 新的治疗方法。我们对隔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 了解病毒与宿主的相互作用和潜在的干预目标。