Systemic and intercellular gene networks underlying RV-induced airways disease

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Respiratory viral infections trigger wheezing illnesses in children and increase the risk that these children will go on to develop asthma. It is now recognized that asthma is not created equal among children. There are different forms of asthma, and risk for asthma is highest among wheezing children who also have allergies. It is currently not well understood why children with wheezing and allergies are more susceptible to respiratory viral infections and more likely to develop asthma. However, an important clue from our previous studies is that the immune factors that are associated with risk versus protection to virus-induced wheezing can be found locally in the airways and lung and also systematically in the blood and bone marrow. This suggested our overarching hypothesis that the immunological mechanisms that determine susceptibility to virus-induced wheezing operate both locally and systemically through a lung-blood-bone marrow axis. Here, we will study systemic immune responses to viruses in children with or without wheezing, allergic inflammation, or both. The research will entail culturing blood-derived immune cells from the children in the presence or absence of a virus. Molecular profiling technologies will be employed to characterize immune responses to the virus at the resolution of single cells, and the responses will be compared and contrasted in groups of children with or without wheezing and/or allergic inflammation. We hypothesize that risk for asthma is determined by the balance of the biological activity of two immune factors that control immune responses to viruses: Interferon regulatory factor 7 (IRF7) and the high-affinity immunoglobulin E receptor subunit gamma (FCER1G). We additionally hypothesize that a highly specialized population of immune cells called dendritic cells control the balance of IRF7 and FCER1G activity. The findings from this study are important because asthma affects 1 in 13 Americans and is the most common chronic disease among children. Each year in the United States, asthma accounts for more than 5 million GP visits, more than 1.5 million visits to the emergency department, and almost 200,000 discharges from hospital inpatient care. Moreover, approximately 11 people die from asthma every day in the United States. Understanding the immunological and molecular factors that determine asthma risk will pave the way for the development of new approaches to treat or prevent asthma and reduce the overall burden of this disease on children and their families.