Long-term Phenotypic Alteration in the Lung Epithelium Following Early-life RSV Infection

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Project Summary/Abstract Severe RSV-bronchiolitis infection has been associated with the development of asthma later in childhood. RSV is the primary cause of bronchiolitis in children worldwide, and it is considered the most impactful risk factor for asthma development among causative pathogens. The therapeutic options are limited. The mechanism by which early-life RSV (EL-RSV) infection predisposes to asthma later in life is unknown. Our studies will investigate the mechanism behind asthma development after EL-RSV infection by focusing on long- term lung epithelial cell alterations generated by epigenetic modification. We will specifically investigate the role of the innate cytokines IL-1β and IL-33 in long-term lung epithelial alteration since we had observed these cytokines highly upregulated during RSV infection. The present proposal provides preliminary data demonstrating that EL-RSV infection generates long-term phenotypic changes in the alveolar epithelial cell type II (AT2) through epigenetic modification in the Il33 gene promoter. These phenotypic changes in the lung epithelium after EL-RSV infection likely modify airway allergic reactions later in life. Additionally, we have identified changes in the ratio of AT2:AT1 cells and altered pulmonary function, suggesting that EL-RSV infection may generate aberrant lung development or repair. Therefore, we will address our hypothesis that EL-RSV infection generates long-lasting lung epithelium alterations that impact lung reactivity to allergens. This leads to the upregulation of innate immune mediators, such as IL-33, that increase the risk of developing respiratory allergies later in life. This hypothesis will be tested by the following specific aims: Aim 1- To determine the acute and persistent mediators and activated pathways responsible for inducing long-term alterations in the lung following EL-RSV infection. We hypothesize that EL-RSV causes long-lasting changes in the lung epithelium, leading to lung functional and structural changes and predisposition to lung pathologies later in life. Aim 2- To investigate the mechanisms underlying long-term changes in the lung epithelium after EL- RSV infection by focusing on the RSV-related immune mediators IL-1β and IL-33. We hypothesize that RSV-related immune mediators IL-1β and IL-33 are critical in generating long-term alteration of the lung epithelial cells. Aim 3- To determine if RSV infection generates epigenetic modifications in the lung epithelial cells that define the long-term alterations in the lung epithelium that contribute to the development of asthma. We hypothesize that EL-RSV infection drives long-term alteration of lung epithelial cells by modifying the chromatin organization and accessibility across the genome through histone modification.