It is now recognized that infection of genetically susceptible individuals with certain respiratory viruses, including human rhinovirus (HRV) and respiratory syncytial virus (RSV), during infancy or early childhood leads to an increased risk of subsequent development of allergic asthma. Survivors of preterm birth, with and without the complication bronchopulmonary dysplasia (BPD), exhibit increased susceptibility to viral infection and greater risk of developing childhood-onset asthma than term infants. In addition, infection of children with allergic asthma with these viruses can severely exacerbate ongoing disease. Despite the recognition of this relationship, the mechanism linking viral infection and susceptibility to and severity of allergic lung inflammation is not known representing a critical unmet need. We have shown that viral infection induces the IL-4Ra-dependent, alternative activation of macrophages (Mf) referred to as ?M2? in lungs of mice that remain long after virus is cleared (~90 days after infection). Fur- thermore, we showed that allergens induce M2 in the lung and that M2 actively mediate enhanced allergic in- flammation. Adoptive transfer of highly purified Mf that express IL-4Ra into IL-4Ra-/- mice resulted in the differ- entiation of M2 in the lung that mitigated virus-induced pro-inflammatory pathology, as part of their repair func- tion. However, they produced Th2-promoting cytokines and actively promoted allergen-induced, Th2-driven al- lergic inflammation associated with asthma. Recent studies demonstrated that M2 Mf polarization is associated with normal alveolar development, and increased M2 polarization protected against hyperoxia-induced lung in- jury in neonatal mice. Based on our recent publications and additional preliminary data described in this appli- cation, we propose the novel hypothesis that enhanced responsiveness to allergen exposure that occurs after viral infection of young mice is in part mediated by long-lived M2. We further propose that virus-induced exacer- bation of ongoing allergic disease is mediated by M2. To test this hypothesis, we will complete the following specific aims: 1) to determine the mechanism for M2 maintenance between virus and allergen exposure; 2) to analyze the specific role of Mfs on the virus-induced enhanced responses to allergen and virus-induced exac- erbation; and 3) to characterize the contribution M2 to enhanced susceptibility of neonates to virus-induced inception of allergic inflammation in vivo. This project will benefit from the expertise and oversight of the 3 PIs. At the conclusion of these studies, we expect to have determined the mechanism by which viral infection leads to development of long-lived M2 that enhance the development of asthma later in life. They will determine whether alterations in lung M2 formation during lung maturation lead to virus-enhanced asthma, thus providing a potential therapeutic target.
Infection of infants and young children with certain types of viruses greatly increases the chance of developing allergic asthma later in life. In addition, viral infection of people with allergic asthma can lead to severe exacerbation of disease. Our research project will analyze how infection with virus controls the differentiation of macrophages. This process is important to understand because macrophages can initiate and amplify the symptoms of asthma. Our proposed studies may identify new targets for the prevention of asthma and severe exacerbations that can develop after a viral infection.
