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

Abstract

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.

Keywords: glucocorticoid receptor (GR); glucocorticoids; inflammation; innate immunity; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); type I interferons (IFNs).

Figure 1

Chemical structure of dexamethasone. Dexamethasone (C₂₂H₂₉FO₅: PubChem CID: 5743) is a synthetic pure glucocorticoid fluorinated at carbon-9 with molecular mass of 392.467 g/mol. Similar to cortisol (hydrocortisone), it has a carbonyl oxygen at carbon-3 and a hydroxyethyl at carbon-21 (as carbon-22). Additionally, it harbors a fluoride (F) at carbon-9 and a methyl at carbon-16 (as carbon-20).

Figure 2

SARS-CoV-2-encoding proteins expressed from its RNA genome. SARS-CoV-2 expresses a total of 29 proteins from its positive-sense single-stranded RNA genome. Open reading frame 1a (ORF1a) and ORF1b are expressed after digestion by the viral protease 16 non-structural proteins (NSPs) in which ORF1a and ORF1b respectively encode 11 proteins (NSP1 to NSP11), and five proteins (NSP12 to NSP16). SARS-CoV-2 also expresses four structural proteins, spike (S), envelop (E), membrane (M), and nucleocapsid (N) proteins, as well as nine accessory factors, ORF3a, 3b, 6, 7a, 7b, 8, 9b, 9c and 10, from their own ORFs. NSP: non-structural protein, ORF: open reading frame, UTR: untranslated region.

Figure 3

Interaction network between the SARS-CoV-2 infection at local tissues, the host immune system and the HPA axis. SARS-CoV-2 initially infects the lung (e.g., respiratory epithelial cells, pneumocyte II and residential macrophages and dendritic cells) and synthesize its new viral particles inside these cells. Infection of the virus to host tissues activates local innate immune system and production of type I IFNs, which in turn stimulate expression of anti-viral ISGs and release of proinflammatory cytokines, and activate adaptive immunity. Such host immune activation leads to induction of the systemic inflammation, which sometimes progresses into multiple organ damage/cytokine release syndrome. Local inflammation as well as circulating proinflammatory cytokines activate the HPA axis, and stimulate secretion of its end-effector cortisol into systemic circulation. The liberated cortisol strongly suppresses tissue inflammation but also inhibits host anti-viral innate immunity. Coincidentially, the virus appears to block the latter effect of cortisol in infected cells by developing glucocorticoid insensitivity during the process of shifting host cell activities toward its own replication. Solid lines indicate positive effects, while dashed lines are for negative effects. ACTH: adrenocorticotropic hormone, CRH: corticotropin releasing hormone, IFN: interferon, ISG: IFN-stimulated genes.

Figure 4

SARS-CoV-2′s life cycle in a host cell and its expected interference with the GR signaling pathway. Upon infection to a host cell, SARS-CoV-2 releases its positive-sense single-stranded genomic (g) RNA into the cytoplasm and initiates synthesis of its RNAs and their encoding proteins. On the other hand, the infection activates local anti-viral innate immune system through host PRRs, which in turn stimulate production/release of type I IFNs. Activated PRRs and released IFNs further stimulate host transcription factors (e.g., NFκB, AP1, STATs and IRFs) for the expression of ISGs and proinflammatory cytokine genes. Some of the produced viral proteins (e.g., NSP6, NSP13, ORF3, and ORF6) shift host cell activities toward viral replication, such as by changing the activities of host kinases, transcription factors, nuclear pore complex, and RNA processing machinery, whereas they downregulate host innate immunity. In the process of modulating host cell activities, SARS-CoV-2 appears to suppress coincidentally the facilitative effects of GR on viral replication by affecting multiple components of its intracellular signaling pathway. Host and viral proteins are indicated with regular and italic letters, respectively. AP1: activator protein-1, GR: glucocorticoid receptor, GRIP1: glucocorticoid receptor-interacting protein-1, IFN: interferon, IRF: interferon regulatory factor, ISG: IFN-stimulated gene, NFκB: nuclear factor of κB, NSP: non-structural protein, ORF: open reading frame, PRR: pattern recognition receptor, STAT: signal transducer and activator of transcription.