A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

Sarohan A. R., KIZIL M., İNKAYA A. Ç., Mahmud S., Akram M., Cen O.

CELLULAR SIGNALLING, vol.87, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 87
  • Publication Date: 2021
  • Doi Number: 10.1016/j.cellsig.2021.110121
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: Vitamin A, Vitamin D, Retinol, Retinoic acid, Retinoid signaling, COVID-19, Type-I IFN, RIG-I, CYP450, NF-kappa B, ROR gamma t, FoxP3, Th17, Treg, Inflammation, Autoimmunity, NF-KAPPA-B, REGULATORY T-CELLS, PATTERN-RECOGNITION RECEPTORS, VITAMIN-A TRANSPORT, TOLL-LIKE RECEPTOR, DENDRITIC CELLS, ACID RECEPTORS, RIG-I, TRANSCRIPTION FACTOR, GENE-EXPRESSION
  • Hacettepe University Affiliated: Yes


The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.