2/1 - Mongolian Center for Environmental & Occupational Health - Mongolia - ABSTRACT In the United States, exposure to fine particulate matter (PM₂.₅) from urban air pollution and increasingly frequent large-scale wildfires poses a growing threat to respiratory health. Despite this, the degree to which PM exposure increases host susceptibility to respiratory viral infections—and the biological pathways involved—remains poorly understood. Addressing this gap is critical, as integrating environmental exposures into infectious disease risk assessment could improve outbreak prediction, clinical management, and targeted prevention for high-risk Americans, including older adults, individuals with chronic respiratory diseases, and overburdened communities. Mongolia offers a unique high-exposure, high-disease setting to investigate this poorly understood interaction, as it suffers from some of the world's highest ambient PM concentrations and frequent epidemics of respiratory viral infections. The overall objective of this U01 project is to determine how PM exposure weakens host immune defenses and increases susceptibility to respiratory viral infections through an integrated, multi-level approach combining epidemiologic, clinical, and mechanistic investigations. The central hypothesis is that PM exposure disrupts airway epithelial integrity, induces oxidative stress and inflammation, and impairs antiviral immune responses, thereby increasing the incidence and severity of respiratory viral infections. To test this hypothesis, we propose three interdependent aims: Aim 1: Characterize the relationship between PM exposure and respiratory viral infection, adjusting for potential confounders. We will conduct multi-year time-series analyses of weekly influenza-like illness (ILI) rates in relation to PM₂.₅ and PM₁₀ concentrations within and across Ulaanbaatar (UB) and Darkhan City (DC). A quasi-experimental framework will leverage Mongolia's coal transition policy (processed coal implementation in UB since 2019 versus continued raw coal use in DC) to strengthen causal inference. Advanced statistical models will adjust for meteorological factors, long-term trends, co-pollutants, and viral circulation. Aim 2: Define individual-level exposure–response relationships between PM exposure, immune dysregulation, and infection outcomes to guide precision public health strategies in Americans. We will conduct longitudinal panel studies in UB and DC (n=100 per site), following participants every 6 months for 3 years. Personal PM₂.₅ exposure will be measured alongside bioaerosol viral exposure and linked to ILI outcomes and immunologic biomarkers, including pro- and anti-inflammatory cytokines and oxidative stress indicators. Aim 3: Elucidate cellular and molecular mechanisms by which PM exposure impairs antiviral defense. Using primary human airway epithelial cells obtained from Aim 2 participants, we will conduct air–liquid interface cell culture experiments to evaluate how PM₂.₅ exposure affects epithelial barrier integrity, cytokine signaling, and type I interferon-mediated antiviral responses following viral stimulation (e.g., TLR3 and TLR7/8 pathways). The findings will deliver three products directly beneficial to the United States: 1) population-level effect estimates linking PM exposure to respiratory infection risk, 2) individual-level exposure–response functions for immune dysregulation and infection outcomes, and 3) mechanistic evidence connecting PM exposure to impaired host antiviral defense. These outputs will inform early warning systems, clinical risk assessment, and biologically informed prevention strategies for Americans at highest risk.
