Human epidemiology and response to SARS-CoV-2 (HEROS)

PROJECT SUMMARY/ABSTRACT (from parent grant)The morbidity and cost to society from childhood viral respiratory illnesses (VRI) is staggering, and allergicrespiratory disease is rampant. In the search for prevention for these common and important diseases,perhaps the solutions are on the farm. Preliminary results from the Wisconsin Infant Study Cohort (WISC)demonstrate that children raised on farms have reduced VRI and atopic dermatitis, and distinct innate immunecell maturation trajectories in early life. Furthermore, in our preliminary studies mononuclear cells from Amishnewborns (high microbial exposure, low rates of allergy) had a more mature phenotype and enhanced antiviralresponses compared to WISC newborns. Collectively, these findings support our central hypothesis: farm-related microbial exposures are associated with increased immune cell maturation, decreased viralrespiratory illness severity, and decreased allergic sensitization. To address this hypothesis, we will enlistour currently enrolled 204 WISC participants (93 farm, 111 non-farm), and enroll additional Amish, WISC farm,and WISC non-farm families (50/group). Our study has three aims that employ cutting-edge technologies andleverage our investigative team's extensive experience with farm medicine, birth cohorts, respiratory virologyand immune development in children. Aim 1: To characterize how farm-related exposures relate to immunedevelopment in early life. We hypothesize that farm-related microbial exposures will prompt increased innateimmune cell maturation and function in early life, including enhanced anti-inflammatory mechanisms. In thesestudies, we will identify farming and microbial effects on immune development of key cells (epithelial cell,plasmacytoid dendritic cell, neutrophil, Tregulatory cells) in the mucosal response to viruses and allergens.Aim 2: To determine how farm exposures affect the burden of VRI and rates of allergic diseases. Wehypothesize that farm-exposed infants have reduced VRI burden and reduced sensitization to commonenvironmental allergens. In these studies, we will use viral diagnostics to determine infections and illnesses,and measure specific IgE to aeroallergens. Aim 3: To define group-specific associations between farm-relatedenvironmental and lifestyle factors, microbial exposure and colonization (nasopharyngeal and stool), immunedevelopment, and clinical outcomes (respiratory illness burden and rates of AD and allergic sensitization). Wehypothesize that house dust from farm homes, particularly Amish households, has more diverse environmentalmicrobiota communities, more diverse microbial colonization of the nasopharynx and gut, and improvedrespiratory health outcomes. In these studies, microbial genomics will be used to identify bacteria and fungi inhousehold dust, nasopharynx, and gut samples, and we will analyze relationships with patterns of immunedevelopment, VRI, and allergy. Completion of these studies will lead to development of novel strategies forenhancing immune development in early life to achieve primary prevention of VRI and allergic diseases.