HDAC Inhibition as Potential Therapeutic Strategy to Restore the Deregulated Immune Response in Severe COVID-19

Abstract

The COVID-19 pandemic has had a devastating impact worldwide and has been a great challenge for the scientific community. Vaccines against SARS-CoV-2 are now efficiently lessening COVID-19 mortality, although finding a cure for this infection is still a priority. An unbalanced immune response and the uncontrolled release of proinflammatory cytokines are features of COVID-19 pathophysiology and contribute to disease progression and worsening. Histone deacetylases (HDACs) have gained interest in immunology, as they regulate the innate and adaptative immune response at different levels. Inhibitors of these enzymes have already proven therapeutic potential in cancer and are currently being investigated for the treatment of autoimmune diseases. We thus tested the effects of different HDAC inhibitors, with a focus on a selective HDAC6 inhibitor, on immune and epithelial cells in in vitro models that mimic cells activation after viral infection. Our data indicate that HDAC inhibitors reduce cytokines release by airway epithelial cells, monocytes and macrophages. This anti-inflammatory effect occurs together with the reduction of monocytes activation and T cell exhaustion and with an increase of T cell differentiation towards a T central memory phenotype. Moreover, HDAC inhibitors hinder IFN-I expression and downstream effects in both airway epithelial cells and immune cells, thus potentially counteracting the negative effects promoted in critical COVID-19 patients by the late or persistent IFN-I pathway activation. All these data suggest that an epigenetic therapeutic approach based on HDAC inhibitors represents a promising pharmacological treatment for severe COVID-19 patients.

Modified Suberoylanilide Hydroxamic Acid Reduced Drug-Associated Immune Cell Death and Organ Damage under Lipopolysaccharide Inflammatory Challenge

“…46 Recent work by Ripamonti et al established the beneficial use of HDAC6 selective inhibitors in attenuating the dysregulated immune responses seen in severe COVID-19 infections by mitigating the associated cytokine storm responses. 47 These studies attributed these beneficial anti-inflammatory properties to its HDAC6 selectivity. Moreover, the reduced pan-selectivity of SAHA-OH could be linked to its anti-inflammatory properties.…”

Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

“…With respect to tinotamustine, a novel repurposing strategy for COVID-19 emerged recently. The accumulation of highly acetylated histones induced by this drug (and compounds with a similar mode of action) results in induction of chromatin remodeling and modulation of gene expression, which has been shown to reset the deregulated immune reaction observed in severe COVID-19, particularly by lowering the uncontrolled inflammatory response (Ripamonti et al, 2022). Thus, the potential polypharmacological effect of tinotamustine in COVID-19, i.e., amelioration of host's cytokine storm and inhibition of viral MPro, merits further investigation.…”

Altered expression of DNA methyltransferases and methylation status of the TLR4 and TNF-α promoters in COVID-19

“…These inhibitors also decrease the activation of monocytes and enhance the differentiation of T cells. A previous study demonstrated the ability of the HDAC inhibitors to hinder IFN-1 expression and downstream effects [ 16 ]. HDAC inhibitors have been found to regulate SARS-CoV-2 entry in epithelial cells by decreasing the expression of angiotensin converting enzyme 2 (ACE2) and blocking ACE2-mediated entry of the virus; consequently, they have been proposed as potential therapeutic agents for COVID-19 [ 16 ].…”

“…A previous study demonstrated the ability of the HDAC inhibitors to hinder IFN-1 expression and downstream effects [ 16 ]. HDAC inhibitors have been found to regulate SARS-CoV-2 entry in epithelial cells by decreasing the expression of angiotensin converting enzyme 2 (ACE2) and blocking ACE2-mediated entry of the virus; consequently, they have been proposed as potential therapeutic agents for COVID-19 [ 16 ]. In our study, there was no significant difference in the expression of HDAC2 and HDAC3 between COVID-19 patients and the control group; however, HDAC3 was associated with severity, with lower expression levels correlating with more-severe disease.…”