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

基本信息

批准号：
10180897
负责人：
Alpana Amalkant Waghmare
金额：
$ 67.27万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10180897
关键词：
Acute Age Allogenic Antiviral Agents 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 design 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 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

项目摘要

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.

项目概要人鼻病毒（HRV）是上呼吸道和下呼吸道中最常见的呼吸道病毒造血细胞移植 (HCT) 受者； 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 HRV 感染带来了很高的疾病负担和观察到的并发症在 HCT 接受者中，HRV 疗法的发展因缺乏全面的研究而受到阻碍了解病毒检测、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，临床危险因素包括血细胞减少症和类固醇的使用，与上呼吸道感染 (URTI) 进展至 LRTI。然而，高达 70% 的患者在感染病毒时患有严重的免疫抑制他们的感染未经治疗。我们的初步数据表明，当时的基因表达特征 URTI 可能预示着进展为 LRTI。我们的目标是描述病毒检测之间的相互作用， HCT 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，以确定与外周血和近端血液中的严重疾病相关的特定细胞群支气管肺泡灌洗液。该提案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，影响疾病感染 HRV 的 HCT 受者的严重程度。这些实验的结果将表征最佳时机和最具预测性的病毒和宿主免疫标记物，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研究了解病毒与宿主的相互作用以及潜在的干预目标。