Dexamethasone for Severe COVID-19: How Does It Work at Cellular and Molecular Levels?

• Main Authors: Tomoshige Kino, Irina Burd, James H. Segars
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: International Journal of Molecular Sciences
• Subjects: glucocorticoids; glucocorticoid receptor (GR); inflammation; innate immunity; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); type I interferons (IFNs)
• Online Access: https://www.mdpi.com/1422-0067/22/13/6764

The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them.