Mechanisms underlying sex differences in allergen- and RSV-induced airway inflammation after in utero allergen exposure.

Vanderbilt University, Nashville TN

Investigators

Abstract

PROJECT SUMMARY Asthma is a common chronic disease among children and is a significant cause of morbidity. As children, males have a higher incidence and prevalence of asthma compared to females at a 2:1 ratio. Yet, it is unknown why there is a sex disparity in asthma prior to the upregulation of sex hormones during puberty. Maternal asthma is a risk factor for childhood asthma, suggesting an in utero effect. Additionally, infection with respiratory syncytial virus (RSV) during the first year of life is also associated with increased risk of developing childhood asthma. The sex difference in airway inflammation in childhood asthma may be regulated at the intersection of genes and environmental exposures, but the mechanisms are unknown. My proposal will determine the mechanistic role of in utero allergen exposures and sex chromosomes in early-life immune responses to respiratory syncytial virus (RSV) infections. I have developed a mouse model of in utero exposure to house dust mite (HDM) allergen followed by RSV infection with 01/2-20 clinical isolate (3x107 PFU/ml) in male and female pups to answer this question. My preliminary data shows that, following infection with RSV, male pups exposed to in utero HDM had increased IL-13+ CD4 T cells and a decreased ratio of Tregs to Th2 cells compared to in utero HDM exposed RSV-infected female pups. Additionally, in bronchoalveolar lavage (BAL) fluid I determined an increased trend (p<0.08) of eosinophils in male pups exposed in utero to HDM following RSV infection compared to females. These results show sex differences in airway inflammation and Treg numbers following in utero exposure to allergen, providing a potential mechanism for the sex disparity in childhood asthma prevalence and severity. Based on these data, I hypothesize that in utero exposure to allergen increases airway inflammation and drives Treg instability and dysfunction in males more than females. I will test my hypothesis using mechanistic approaches that examine the differential contributions of sex chromosome dosages versus sex hormones to airway inflammation by using the “four core genotypes” (FCG) mice. FCG mice allow for XY phenotypic females and XX phenotypic males due to mutations in the Sry gene on the Y chromosome. In this proposal, I will: (Aim 1) Elucidate how the X chromosome restricts RSV-induced airway inflammation in pups exposed to allergen in utero, and (Aim 2) Determine how the X chromosome increases Foxp3 expression and Treg suppressive function in pups exposed to in utero allergen. Understanding how allergens and sex chromosomes impact immune-mediated responses in early life is critical for generating new prevention and treatment approaches that target the early life immune system in utero and postnatally.