Immunomodulatory LncRNA on antisense strand of ICAM-1 augments SARS-CoV-2 infection-associated airway mucoinflammatory phenotype
Dinesh Devadoss,
Arpan Acharya,
Marko Manevski,
Dominika Houserova,
Michael D. Cioffi,
Kabita Pandey,
Madhavan Nair,
Prem Chapagain,
Mehdi Mirsaeidi,
Glen M. Borchert,
Siddappa N. Byrareddy,
Hitendra S. Chand
Affiliations
Dinesh Devadoss
Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
Arpan Acharya
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
Marko Manevski
Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
Dominika Houserova
Department of Pharmacology, University of South Alabama, Mobile, AL 36688, USA
Michael D. Cioffi
Department of Physics, Florida International University, Miami, FL 33199, USA
Kabita Pandey
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
Madhavan Nair
Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
Prem Chapagain
Department of Physics, Florida International University, Miami, FL 33199, USA; Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA
Mehdi Mirsaeidi
Miller School of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Miami, Miami, FL 33136, USA
Glen M. Borchert
Department of Pharmacology, University of South Alabama, Mobile, AL 36688, USA
Siddappa N. Byrareddy
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; Corresponding author
Hitendra S. Chand
Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; Corresponding author
Summary: 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 IL-6, ICAM-1, CXCL-8, and SCGB1A1 inflammatory factors; MUC5AC and MUC5B mucins; and SPDEF, FOXA3, and FOXJ1 transcription factors in COVID-19 patient nasal samples compared with uninfected controls. A lncRNA on antisense strand to ICAM-1 or LASI 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 LASI lncRNA. Notably, blocking LASI lncRNA reduced the SARS-CoV-2 replication and suppressed MUC5AC mucin levels and associated inflammation, and select LASI-dependent miRNAs (e.g., let-7b-5p and miR-200a-5p) were implicated. Thus, LASI lncRNA represents an essential facilitator of SARS-CoV-2 infection and associated airway mucoinflammatory response.
