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

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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.