Long-term alteration of the airway epithelium after early life RSV infection

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. There is currently no vaccine approved, and

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 alteration generated by epigenetic modification.

We will specifically investigate the role of the innate cytokines IL-1 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 and Ilr1 promoters. These phenotypic changes in the lung epithelium after EL-RSV infection likely modify airway allergic reactions later in life. Thus, we will address our hypothesis that EL-RSV infection generates long-lasting lung epithelium

alterations that impact lung responsiveness to allergens. This leads to the upregulation of innate immune mediators, such as IL-33, that increase the risk of developing airway allergies later in life. This hypothesis will be tested by the following specific aims: Aim 1- To define whether EL-RSV infection generates long-lasting changes in the lung epithelium that leads to

subsequent allergic disease. We hypothesize that EL-RSV causes long-lasting changes in the lung epithelium, which modify the lung epithelial cell's phenotype in the lung, leading to lung functional changes and respiratory allergies later in life. Aim 2- To determine if RSV infection generates epigenetic modifications

in the lung epithelial cells that generate long-term alterations in the lung epithelium responsiveness. We hypothesize that RSV infections drive lung epithelial cell long-term alteration by modifying the chromatin organization and accessibility across the genome through histone modification. Aim 3- To identify the

mechanisms involved in generating the long-term alteration in the lung epithelium by focusing on the positive feedback loop between IL-1 and IL-33 during RSV infection. Our working hypothesis is that the IL- 1/IL-33 upregulation during EL-RSV infection is critical for generating long-lasting modification in the lung

epithelium that may promote phenotypic alterations in the respiratory epithelium by epigenetic modification. We hypothesize that EL-RSV infections drive airway epithelial cell alteration by modifying the organization and accessibility of the chromatin across the genome by histone modification. Understanding these mechanisms will

be crucial for developing interventional therapies that attenuate RSV disease severity and the predisposition to childhood asthma.