Effect of Air Pollution on the Immune Response to Respiratory Viral Infection in Adults

这项拟议的以患者为导向的导师研究职业发展奖将支持克罗夫特博士的 研究空气污染对机体免疫反应影响的内科研究进展 呼吸道病毒感染(RVI)。具体地说，克罗夫特博士提出的研究为被导师提供了一个机会 先进的环境流行病学方法、暴露评估、免疫系统的发展 转录学和研究团队管理。轮状病毒是#年发病率和死亡率的严重原因。 成年人。PM2.5与燃烧相关的空气污染(黑碳：交通污染的标志)已被联系在一起 RVI的住院率上升。然而，空气污染可能通过的免疫机制 增加成人对严重RVIs(即需要住院)的易感性仍不清楚。克罗夫特医生的 最重要的假设是，短期暴露于环境空气污染会增加患严重肺炎的风险 记录成人呼吸道病毒感染，通过扰乱关键基因途径(例如，核因子-κB和干扰素-γ) 先天免疫反应。为了验证这一假设，克罗夫特博士将招募患有严格疾病住院的患者。 来自一项关于改善呼吸道诊断的活跃R01研究的微生物学证明的RVI判定 感染。在这群RVI患者中，他将领导分析，探索短期内 多种空气污染物浓度和特定来源污染物浓度的增加与 因特定RVI(例如流感或呼吸道合胞病毒)而住院的比率。在相同的人口中 患者，他将确定这些污染物暴露是否与激活或抑制 关键的先天免疫途径。具体地说，使用一组有临床诊断的患者 他的研究将使用病例交叉设计来估计与以下疾病相关的RVI住院率 前28天颗粒物和气态污染物浓度急剧增加(目标1)。病人 确诊感染的患者将接受外周血的RNA转录图谱分析，从而允许克罗夫特博士还 检查污染物浓度的短期增加与基因之间的关系 在先天免疫系统中的表达(目标2)。在这两个目标中，我们将确定这种反应是否 在COPD或哮喘患者中，可能是性别特定的、种族或民族特定的或独特的。这项研究可能 立即受益于接触空气污染患者的临床咨询，也可能有助于指导 未来的空气质量政策，以最大限度地减少易受RVI影响的人群的风险。最后，研究结果将 提供有价值的数据，作为未来空气污染对呼吸系统影响的前瞻性研究的基础 感染和先天免疫。他的导师包括环境流行病学专家(大卫·里奇，SCD)， 病毒学(Ann Falsey，医学博士)和转录学(Thomas Mariani，博士)。克罗夫特博士的高效导师 团队，包括多个内容特定的导师，将帮助他发展成为独立的 从事吸入毒素对呼吸健康影响的临床研究的调查员。

This proposed Mentored Patient-Oriented Research Career Development Award will support Dr. Croft's advancement as a physician-researcher studying the effects of air pollution on the immune response to respiratory viral infection (RVI). Specifically, Dr. Croft's proposed study provides an opportunity for mentored development in advanced environmental epidemiology approaches, exposure assessment, immune system transcriptomics, and research team management. RVIs are a serious cause of morbidity and mortality in adults. PM2.5 and combustion related air pollution (black carbon: a marker of traffic pollution) have been linked to an increased rate of hospitalizations for RVI. However, the immune mechanisms by which air pollution may enhance susceptibility to severe RVIs (i.e. requiring hospitalization) in adults remains unclear. Dr. Croft's overarching hypothesis is that short-term exposure to ambient air pollution increases the risk of a severe documented respiratory viral infection in adults, by disrupting key gene pathways (e.g. NF-κB and IFN-γ) within the innate immune response. To test this hypothesis, Dr. Croft will enroll patients hospitalized with rigorously adjudicated, microbiologically proven RVI from an active R01 study on improved diagnostics for respiratory infection. In this population of patients with RVI, he will then lead analyses to explore whether short-term increases in multiple air pollutant and source-specific pollutant concentrations are associated with an increased rate of hospitalization for specific RVIs (e.g. influenza or respiratory syncytial virus). In the same population of patients, he will determine whether these pollutant exposures are associated with activation or suppression of key innate immune pathways. Specifically, using a population of patients with clinically adjudicated diagnoses of RVI, his study will use a case-crossover design to estimate the rate of RVI hospitalizations associated with acute increases in the concentration of particulate and gaseous pollutants in the prior 28 days (Aim 1). Patients with confirmed infection will undergo RNA transcriptional profiling of peripheral blood, allowing Dr. Croft to also examine the association between the same short-term increases in pollutant concentrations and gene expression within the innate immune system (Aim 2). In both aims, we will determine whether this response may be sex-specific, race or ethnicity specific or unique in patients with COPD or asthma. This study may immediately benefit the clinical counseling of patients with exposure to air pollution and may also help guide future air quality policies to minimize the risk to populations vulnerable to RVI. Finally, the study results will provide valuable data upon which to base a future prospective study of the effects of air pollution on respiratory infection and innate immunity. His mentors include experts in environmental epidemiology (David Rich, ScD), virology (Ann Falsey, MD) and transcriptomics (Thomas Mariani, PhD). Dr. Croft's highly productive mentor team, including multiple content specific mentors, will help support his development into an independent investigator pursuing clinical research on the respiratory health effects of inhaled toxins.