Dexamethasone for severe covid‐19: How does it work at cellular and molecular levels?

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 lifethreatening viral diseases, probably due to a difference in specific virally‐encoded molecules and host cell activities modulated by them.