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.
Highlights
Recent successful development of SARS-CoV-2 vaccines provided hope to reduce remains an urgent issue for treatment of already ill patients, because it will take new infections by SARS-CoV-2, but identification of the effective therapeutic compounds considerable time to achieve world-wide herd immunity and there is a possibility that the remains an urgent issue for treatment of already ill patients, because it will take considervirus may mutate into a resistant strain before it can be eliminated [9]
After successful infection to host cells, SARS-CoV-2 expresses, from several open reading frames (ORFs) of its genomic RNA, a total of 29 proteins that consist of four structural proteins, sixteen non-structural proteins (NSPs), and nine accessory factors [38,39,40,41]
IFN-mediated innate immunity or have in their circulation auto-antibodies that bind to and neutralize type I IFNs [69,70,71,72]. These patients demonstrate aberrant elevation of the cytokines functional against fungal and/or parasite infections [67]. These pieces of evidence strongly suggest that an insufficient host type I IFN-mediated anti-viral immunity and subsequent failure in eradicating SARS-CoV-2 infection are key for progressing into severe COVID-19
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In December 2019, highly infectious but less pathogenic SARS-CoV-2 invaded a human community at Wuhan, China, possibly from its reservoir animal bats [5,6]. Recent successful development of SARS-CoV-2 vaccines provided hope to reduce remains an urgent issue for treatment of already ill patients, because it will take new infections by SARS-CoV-2, but identification of the effective therapeutic compounds considerable time to achieve world-wide herd immunity and there is a possibility that the remains an urgent issue for treatment of already ill patients, because it will take considervirus may mutate into a resistant strain before it can be eliminated [9]. The endogenous form, cortisol, is the end product of the stress-responsive effective for COVID-19 among many other life-threatening infectious diseases, such as hypothalamic-pituitary-adrenal (HPA) axis [18,19]. We compare COVID-19 responses to those of other pathogens/viruses for which glucocorticoids show no therapeutic benefit
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