Immunomodulatory LncRNA on Antisense Strand of ICAM-1 Augments SARS-CoV-2 Infection-associated Airway Mucoinflammatory Phenotype

Noncoding RNAs are important regulators of mucoinflammatory response, but little is known about the contribution of airway long noncoding RNAs (lncRNAs) in COVID-19. RNA-seq analysis showed a more than 4-fold increased expression of , , , and inflammatory factors; and  mucins; and , , and transcription factors in COVID-19 patient nasal samples compared with uninfected controls. A lncRNA on antisense strand to ICAM-1 or was induced 2-fold in COVID-19 patients, and its expression was directly correlated with viral loads. A SARS-CoV-2-infected 3D-airway model largely recapitulated these clinical findings. RNA microscopy and molecular modeling indicated a possible interaction between viral RNA and lncRNA. Notably, blocking lncRNA reduced the SARS-CoV-2 replication and suppressed MUC5AC mucin levels and associated inflammation, and select -dependent miRNAs (e.g., let-7b-5p and miR-200a-5p) were implicated. Thus, lncRNA represents an essential facilitator of SARS-CoV-2 infection and associated airway mucoinflammatory response.