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Principal Investigator: Madepalli Krishnappa Lakshmana
Organization: FLORIDA INTERNATIONAL UNIVERSITY
Fiscal Year: 2020
Award: $195,353
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT
Airway epithelial cells or AECs orchestrate the pulmonary immune responses to airborne viral infections and
drive the successful resolution of infection. Among the immediate early responders that set the tone for innate
immune 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/receptors
that help recruit immune cells. As with the other acute viral infections, a balanced early epithelial response
provides timely recruitment of appropriate immune cells to thwart the infection and resolve the lung tissue
remodeling. However, hosts with hyperreactive or compromised lung mucosal immunity, suffer from higher lung
tissue 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 might
predispose 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 the
immediate early susceptibility factors of upper airway epithelial cells to SARS-CoV-2 that contribute to a
dysregulated inflammatory response. Specifically, the archived biological samples from COVID-19 patients will
be 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 cytospins
and cell pellets will be analyzed for host cellular (lncRNA and receptors) and viral (Spike protein) factors; and
will be validated by qPCR analysis. We will confirm the role of lncRNA by molecular gene editing in AECs cultured
in-vitro and treated with a pseudovirions expressing SARS-CoV-2 S protein and validated in separate studies
using SARS-CoV-2 clinical isolate for infection. Levels of inflammatory factors will be analyzed by multianalyte
assays. This proof of concept study will help establish the association of novel lncRNAs with COVID-19
pathophysiology that could serve as early biological indicators (biomarkers) of airway immune dysregulation and
other comorbidities. Molecular studies will also help determine whether targeting the novel lncRNA can help
reduce or suppress SARS-CoV-2 mediated airway inflammatory responses.
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