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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：
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
项目类别：
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

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.