ABSTRACT In recent decades, Mongolia has experienced major economic and environmental changes, and suffered from severe air pollution. Ulaanbaatar (UB) and Darkhan City (DC) have some of the highest ambient particulate matter (PM) concentrations in the world and frequently suffer epidemics of viral respiratory diseases. The associations between PM exposure and cardiorespiratory mortality and morbidity have been well documented, with an established 6.67 million premature deaths globally attributed to air pollution in 2019. Recently, attention has increased regarding the association of PM pollution and respiratory viral infection. Hence, this U01 proposal, as part of the Mongolian GEOHealth Hub program, focuses on studying the relationships and interactions between PM exposure and respiratory viral infections. The U01 project consists of a main study and two pilot studies to begin Center activities. The main project is designed to test the hypothesis that PM exposure weakens the immune defense against respiratory viral infection. It has three interconnected specific aims. Aim 1 is to characterize the relationship between PM exposure and respiratory viral infection through a time-series analysis of weekly influenza-like illness (ILI) rates in association with PM levels within and across UB and DC, adjusting for potential confounders and co-pollutants. As an air pollution control measure, UB started the implementation of processed coal use in May, 2019, whereas DC continues to use raw coal. Nesting this policy intervention into the time-series analysis strengthens the causal inference of the PM-ILI association derived from natural variabilities over time. Aim 2 is to examine immunologic and viral responses to personal PM exposure through two parallel panel studies in residents of UB and DC, respectively. Each panel consists of 100-120 nonsmoking adults who will be measured semiannually during a 3-year follow-up period. ILI counts and immunologic biomarkers will be associated with personal PM exposures. Aim 3 is to define the direct effects of PM exposure on epithelial integrity and immune signaling and the subsequent impact on anti-viral responses. This will be achieved through cell culture studies that are directly linked to Aim 2 subjects (as cell donors). The two pilot studies, built upon the Aim 2 main study, aim to explore the effects of PM on pulmonary tuberculosis and bone mineral loss, respectively. These studies are motivated by high prevalence of both tuberculosis and osteoporosis in Mongolia and by emerging evidence suggesting PM or heavy metals in PM as risk factors. This U01 proposal is an interdisciplinary research project involving researchers in epidemiology, toxicology, environmental and occupational health, exposure science, biostatistics, virology, immunology, environmental engineering, respiratory medicine, and infectious disease from multiple institutions in Mongolia, Duke University, and Duke Kunshan University. The U01 research is designed to be the initial main platform for engaging U2R Fellows (trainees) and Faculty (mentors) in research and training. 1

PROJECT NARRATIVE This project uses a multidisciplinary approach, integrating epidemiologic observational studies and laboratory cell-model toxicology experiments, to investigate whether and how particulate matter air pollution affect respiratory viral infections. Ancillary pilot study projects will explore the impact of particulate pollution on pulmonary tuberculosis and osteoporosis. Mongolia has high prevalence and incidence of these diseases and high particulate matter levels in the world.