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: 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
• 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

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.

项目摘要 人鼻病毒（HRV）是在上和下呼吸道中检测到的最常见的呼吸病毒 在造血细胞移植（HCT）受体中； HRV下呼吸道感染后的死亡率 与已知的肺病毒病原体（包括呼吸道合胞病毒，流感， 和Parainfluenza病毒。尽管疾病负担很大，并且观察到的HRV感染并发症 在HCT接受者中，缺乏全面的HRV治疗剂的发展受到阻碍 了解病毒检测，症状和宿主免疫反应与 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 细胞质和类固醇的使用与从上呼吸道感染（URTI）到 lrti。但是，在征收病毒时，多达70％的患有深层免疫抑制的患者 他们的感染未经治疗。我们的初步数据表明，基因表达在 URTI可能可以预测到LRTI的发展。我们旨在表征病毒检测之间的相互作用， 前瞻性HCT受体中HRV感染期间早期的细胞因子水平和细胞免疫反应 监视队员。我们还将在单个细胞水平上进行深度基因表达分析以识别 在外周血和近端与严重疾病有关的特定细胞种群 支气管肺泡灌洗液。该提议的中心假设是病毒和宿主免疫动力学， 在特定组织室中包括全球和细胞特异性基因表达谱，影响疾病 HRV感染的HCT接受者的严重程度。这些实验的结果将表征最佳 时间和最预测的病毒和宿主免疫标记，可用于设计合理的临床试验 新颖的治疗学。我们对隔室和细胞特定免疫反应的深刻询问将进一步 了解病毒宿主相互作用和干预措施的潜在目标。