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Clinical response to rhinovirus challenge in human asthmatics

人类哮喘患者对鼻病毒攻击的临床反应

基本信息

批准号：
9893778
负责人：
LARRY C BORISH
金额：
$ 69.98万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-13 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893778
关键词：
Address Adenoidal structure Allergic Allergic rhinitis Antiviral Agents Apoptotic Asthma Automobile Driving Biology Biopsy Blood Circulation Bronchial Hyperreactivity CCL11 gene CXCL1 gene Cell Death Cells Cessation of life Child Clinical Defect Development Diffuse Eosinophilia Epigenetic Process Epithelial Epithelial Cells Epithelium Etiology Evolution Extrinsic asthma Gene Expression Profile Human Human Volunteers Immune Immune response Immune system Immunity Immunology In Vitro Individual Infection Inflammatory Inflammatory Response Interferon-alpha Interferons Interleukin-15 Measures Mediator of activation protein Modification Molecular Monitor Morbidity - disease rate Nasal Epithelium Nature Necrosis Nose Pathology Pathway interactions Patients Pattern Predisposition Process RANTES Reaction Research Personnel Respiratory Signs and Symptoms Rhinovirus Rhinovirus infection Role Severities Sputum Symptoms TLR3 gene TLR7 gene TSLP gene Testing Time Universities Viral Viral Load result Virginia Virus Diseases Vision adaptive immune response adverse outcome airway epithelium airway inflammation allergic airway disease antiviral immunity asthma exacerbation asthmatic asthmatic airway clinical investigation cohort cytokine design eosinophil expectation immunoregulation in vivo neutrophil prevent public health relevance recruit response virology young adult

项目摘要

DESCRIPTION (provided by applicant): Most asthma exacerbations in children and young adults result from rhinovirus (RV) infections. As the most important cause of asthma-related morbidity it is essential that clinical investigations be performed in humans to define the underlying mechanisms. We hypothesize that the immune responses generated in the nose of asthmatics underlie subsequent systemic modulation of the immune system, and that - in susceptible individuals (those with pre-existing asthma) - this modified nasal milieu is responsible for the asthma exacerbation. We propose that this modification produces a distinct pattern of immune responsiveness to RV in the upper airway of allergic rhinitis (AR) and asthmatic cohorts, which triggers the development of a Th2 cytokine signature state that drives the adverse outcome of RV infection in the lower airway of asthmatics (but not in those with AR). In addition, we propose that the intensity of this Th2-inducing nasal airway milieu is further exaggerated in these allergic cohorts, by a concomitant defect in the development and expression of effective anti-RV immune responses, leading to greater susceptibility to RV. Specific Aim 1 will address the hypothesis that epigenetic changes develop in nasal epithelial cells (EC) during the evolution of allergic airway disease as a result of which nasal EC are programmed to produce cytokines central to orchestrating an allergic inflammatory immune response. We will primarily determine whether nasal epithelium from AR and allergic asthmatic cohorts, when infected with RV, is programmed to secrete cytokines that promote a Th2 cytokine "signature" (IL-25, IL-33, and TSLP). Specific Aim 2 will interrogate the complementary hypothesis that increased susceptibility to RV and extent of nasal infections in AR and asthmatics amplifies the consequences of this Th2-inducing bias. And that in the asthmatics this will correspond to worsening lower airway symptoms and inflammation. Specifically we propose that over time nasal epithelium in AR and asthma is epigenetically re-programmed, resulting in the greater susceptibility of EC to RV infection. Initially we will analyze nasal EC ex vivo to tes the hypothesis that EC from AR and asthmatics will be more susceptible to RV infection as manifested by a greater magnitude of RV replication, a more rapid tempo of infection and overall greater death of RV-infected cells. We will then corroborate this in vitro analysis with in vivo studies by infecting AR, asthmatics and controls with RV, monitoring viral load over time as a measure of the pace of infection. Most importantly, we will perform nasal biopsies at the peak of infection to determine the extent of viral infection and whether this represents cytopathic (necrotic) or apoptotic cell death. And, finally, Specific Aim 3 will address the molecular and cellular basis for the defect in anti-viral immunity in asthma. We will establish primary cultures f EC from control, AR, and asthmatic individuals prior to RV infection and examine them for baseline- and RV infection-induced expression of cytokines central to anti-viral immunity. We expect that anti-viral mediator expression will correlate inversely with the susceptibility, tempo, and severity of RV infection.

描述(申请人提供)：大多数儿童和年轻人的哮喘恶化是由鼻病毒(RV)感染引起的。作为哮喘相关发病率的最重要原因，在人类身上进行临床调查以确定潜在的发病机制是至关重要的。我们假设，哮喘患者鼻子中产生的免疫反应是随后免疫系统的系统调节的基础，而在易感人群(既往患有哮喘的人)中，这种改变的鼻部环境是哮喘恶化的原因。我们认为，这种修饰在变应性鼻炎(AR)和哮喘患者的上呼吸道对RV产生了不同的免疫应答模式，这触发了Th2细胞因子签名状态的发展，从而驱动哮喘患者(但不是AR患者)下呼吸道RV感染的不良后果。此外，我们认为这种Th2诱导的鼻腔呼吸道环境的强度进一步在这些过敏性队列中，由于有效的抗RV免疫反应的发展和表达的伴随缺陷而被夸大，导致对RV的更大易感性。具体目标1将解决这一假设，即在过敏性呼吸道疾病的演变过程中，鼻腔上皮细胞(EC)发生表观遗传变化，其结果是鼻腔上皮细胞被编程产生细胞因子，以协调变态反应性炎症免疫反应。我们将首先确定AR和过敏性哮喘队列的鼻黏膜上皮在感染RV时是否被编程为分泌促进Th2细胞因子“签名”的细胞因子(IL-25、IL-33和TSLP)。特定目标2将询问补充假设，即AR和哮喘患者对RV的易感性增加以及鼻部感染的程度会放大这种Th2诱导偏向的后果。而在哮喘患者中，这将对应于下呼吸道症状和炎症的恶化。具体地说，我们认为随着时间的推移，AR和哮喘的鼻黏膜上皮细胞被表观遗传学重新编程，导致EC对轮状病毒感染的易感性更高。首先，我们将对鼻腔内皮细胞进行体外分析，以验证以下假设：AR和哮喘患者的鼻腔内皮细胞更容易受到RV感染，表现为RV复制的幅度更大，感染速度更快，RV感染细胞总体上死亡更多。然后我们将用In来证实这一体外分析活体研究通过用轮状病毒感染AR、哮喘患者和对照组，监测一段时间内的病毒载量，作为感染速度的衡量标准。最重要的是，我们将在感染高峰期进行鼻部活检，以确定病毒感染的程度，以及这是否代表细胞病变(坏死性)或凋亡性细胞死亡。最后，特殊目标3将解决哮喘患者抗病毒免疫缺陷的分子和细胞基础。我们将在RV感染前建立对照组、AR和哮喘患者的EC原代培养，并检测基线和RV感染诱导的抗病毒免疫中心细胞因子的表达。我们预计，抗病毒介体的表达将与易感性、节奏、以及轮状病毒感染的严重程度。