HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells

Abstract

BackgroundDespite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases.ResultsAim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription.ConclusionThis study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.

Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype

“…The reduced levels of CXCL10 were explained by the control exerted by both the type I IFN and IFN-γ pathways on the expression of this chemokine in fibroblasts ( Ohta et al., 2014 ; Yu et al., 2020 ). Besides inhibiting type I response, MS-275 was recently demonstrated to favor SARS-CoV-2 infection in MCs by modulating ACE2 and TMPRSS2 expression ( Trionfetti et al., 2023a ). Overall, these results strongly suggest that treatment with HDAC1-3 inhibitor MS-275 may favor viral infection by multiple mechanisms.…”

“…Moreover, several reports demonstrated that HDACs are implicated in the pathogenesis of viral infections ( Herbein and Wendling, 2010 ; Panella et al., 2016 ; Trionfetti et al., 2023a ). Lipopolysaccharide (LPS) stimulation was demonstrated to enhance HDAC3 activity, leading to tumor necrosis factor-α (TNF-α) production ( Zhu et al., 2010 ).…”

The Human Genetic Differences in the Outcomes of mRNA Vaccination against COVID-19: A Prospective Cohort Study

“…In this regard, HDAC6 inhibitors were found to reduce cytokine release, decrease T cell exhaustion, and contribute to innate immune cell memory processes, potentially providing therapeutic benefits in severe COVID-19 cases. On the other hand, a study exploring how HDAC inhibition affects SARS-CoV-2 infection in mesothelial cells revealed that blocking HDAC1-3 actually boosts SARS-CoV-2 cell entry, replication, and production [ 50 ]. Additionally, another investigation on a different RNA virus, influenza A virus, showed that suppressing HDAC6 activity leads to an elevated virus titer [ 51 ].…”

“…To sum up, the key implication drawn is the necessity for a precise understanding and control of HDAC. While most drugs targeting HDAC have functioned as inhibitors, concentrating on pathological conditions where gene overexpression is a therapeutic target [ 53 , 54 ], our findings reveal that HDAC can contribute positively to the immune response at suitable expression levels, and inhibition might be detrimental [ 50 , 51 ]. This emphasizes the significance of delving into and managing the appropriate expression level and emphasizes the requirement for a precise comprehension of each specific class of HDAC, given its pervasive impact on the entire body.…”