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

• 批准号: 9081696
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-13 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081696
• 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; Eosinophilia; Epigenetic Process; Epithelial; Epithelial Cells; Etiology; Evolution; 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; Role; Severities; Sputum; Symptoms; TLR3 gene; TLR7 gene; TSLP gene; Testing; Time; Universities; Viral; Viral Load result; Virginia; Virus Diseases; Vision; adaptive immunity; adverse outcome; airway inflammation; allergic airway disease; antiviral immunity; asthmatic; asthmatic airway; base; clinical investigation; cohort; cytokine; design; eosinophil; expectation; in vivo; prevent; programs; public health relevance; response; virology; young adult

 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（由申请方提供）：大多数儿童和年轻人的哮喘急性发作是由鼻病毒（RV）感染引起的。作为哮喘相关发病率的最重要原因，在人类中进行临床研究以确定潜在机制至关重要。我们假设哮喘患者鼻内产生的免疫反应是随后免疫系统系统调节的基础，并且在易感个体（先前存在哮喘的个体）中，这种改变的鼻环境是哮喘恶化的原因。我们认为，这种修饰在过敏性鼻炎（AR）和哮喘队列的上气道中产生了对RV的免疫应答的独特模式，这触发了Th 2细胞因子特征状态的发展，该状态驱动了哮喘患者下气道中RV感染的不良结果（但不是AR患者）。此外，我们提出，这种Th 2诱导的鼻气道环境的强度进一步增加。 在这些过敏性队列中，由于有效抗RV免疫应答的发展和表达中的伴随缺陷而被夸大，导致对RV的更大易感性。具体目标1将解决这样的假设，即在过敏性气道疾病的演变过程中，鼻上皮细胞（EC）中发生表观遗传变化，因此鼻EC被编程为产生细胞因子，这些细胞因子对于协调过敏性炎症免疫应答至关重要。我们将主要确定当感染RV时，AR和过敏性哮喘队列的鼻上皮是否被编程为分泌促进Th 2细胞因子“特征”（IL-25、IL-33和TSLP）的细胞因子。具体目标2将询问补充假设，即AR和哮喘患者对RV的易感性增加和鼻腔感染程度放大了这种Th 2诱导偏倚的后果。在哮喘患者中，这将对应于下呼吸道症状和炎症的恶化。具体来说，我们认为随着时间的推移，AR和哮喘的鼻上皮细胞表观遗传学重新编程，导致EC对RV感染的易感性增加。最初，我们将分析鼻EC离体测试的假设，EC从AR和哮喘将更容易受到RV感染，表现为更大幅度的RV复制，更快的感染克里思和整体更大的RV感染细胞的死亡。然后我们将证实这一体外分析与在 通过用RV感染AR、哮喘患者和对照进行体内研究，随时间监测病毒载量作为感染速度的量度。最重要的是，我们将在感染高峰期进行鼻活检，以确定病毒感染的程度，以及这是否代表细胞病变（坏死）或凋亡细胞死亡。最后，特异性目标3将解决哮喘抗病毒免疫缺陷的分子和细胞基础。我们将在RV感染前建立来自对照、AR和哮喘个体的EC的原代培养物，并检查它们的基线和RV感染诱导的对抗病毒免疫至关重要的细胞因子表达。我们预期抗病毒介质的表达将与易感性，克里思， 和RV感染的严重程度。