Novel long noncoding RNAs in the airway mucous response

Airway epithelial cells or AECs orchestrate the pulmonary immune responses to airborne viral infections anddrive the successful resolution of infection. Among the immediate early responders that set the tone for innateimmune response, we have identified that as early as half-an-hour of insult, the long noncoding RNA species(lncRNAs) are deployed by the AECs to modulate the epithelial inflammatory response. Specifically, in AECs,we identified a few novel lncRNAs that modulate the expression of inflammatory factors and of ligand/receptorsthat help recruit immune cells. As with the other acute viral infections, a balanced early epithelial responseprovides timely recruitment of appropriate immune cells to thwart the infection and resolve the lung tissueremodeling. However, hosts with hyperreactive or compromised lung mucosal immunity, suffer from higher lungtissue damage, impaired lung functions and overall poor health outcome, as noted in several cases of COVID-19 patients. Overarching goal is to identify and characterize the early host immunomodulatory factors that mightpredispose to severe hyperinflammatory state to novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 disease. The studies proposed will provide novel insight into theimmediate early susceptibility factors of upper airway epithelial cells to SARS-CoV-2 that contribute to adysregulated inflammatory response. Specifically, the archived biological samples from COVID-19 patients willbe analyzed to establish the association of expression levels of the novel lncRNA and SARS-CoV-2 receptors(ACE2 and TMPRSS2) among individuals with various degree of COVID-19 disease severity. The fixed cytospinsand cell pellets will be analyzed for host cellular (lncRNA and receptors) and viral (Spike protein) factors; andwill be validated by qPCR analysis. We will confirm the role of lncRNA by molecular gene editing in AECs culturedin-vitro and treated with a pseudovirions expressing SARS-CoV-2 S protein and validated in separate studiesusing SARS-CoV-2 clinical isolate for infection. Levels of inflammatory factors will be analyzed by multianalyteassays. This proof of concept study will help establish the association of novel lncRNAs with COVID-19pathophysiology that could serve as early biological indicators (biomarkers) of airway immune dysregulation andother comorbidities. Molecular studies will also help determine whether targeting the novel lncRNA can helpreduce or suppress SARS-CoV-2 mediated airway inflammatory responses.