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Front Immunol ; 13: 841716, 2022.
Article in English | MEDLINE | ID: covidwho-1855353


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.

COVID-19 , Histone Deacetylase Inhibitors , COVID-19/drug therapy , COVID-19 Vaccines , Cytokines/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/metabolism , Humans , Immunity , Pandemics , SARS-CoV-2
J Mol Biol ; 434(6): 167277, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-1440208


Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses.

COVID-19 , Flavivirus , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Flavivirus/genetics , Histone Deacetylases , Humans , Interferons/genetics , Membrane Proteins , RNA-Binding Proteins , Repressor Proteins , SARS-CoV-2 , Virus Replication/genetics , Zika Virus/genetics , Zika Virus Infection/genetics
Rev Physiol Biochem Pharmacol ; 180: 1-47, 2021.
Article in English | MEDLINE | ID: covidwho-1396975


Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins.Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer.This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.

Histone Deacetylases , Monocytes , Epigenesis, Genetic , Histone Deacetylase Inhibitors , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Histones/metabolism , Monocytes/metabolism
Genes (Basel) ; 11(5)2020 05 15.
Article in English | MEDLINE | ID: covidwho-828732


Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.

Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/genetics , Neoplasms/genetics , Transcription Factors/genetics , Antineoplastic Agents/therapeutic use , Histones/genetics , Humans , Neoplasms/therapy , Substrate Specificity/genetics
Rev Fac Cien Med Univ Nac Cordoba ; 77(2): 117-125, 2020 06 16.
Article in Spanish | MEDLINE | ID: covidwho-617022


Introduction: The NAD+dependent proteins deacetylases are called Sirtuins (SIRT). Objectives: Objectives: this review is to study the sirtuins involved in cancer, as well as SIRT1 inhibition studies in patients with coronavirus disease COVID-19. Data source and selection: For this, a search was made in Medline, Scopus and WOS, where descriptive studies of each of the functions of sirtuins were included, adjusted to recent scientific research. SIRT1 inhibition reduces CD8 T cell cytotoxicity in patients with systemic erythematosus lupus, being susceptible to SARS Cov-2 infections. SIRT2 is regulated by the secretion of IL-4 by eosinophils and the increase in SIRT2 increases hyperplasia, in contrast, SIRT3 promotes angiogenesis, inducing cardiac remodeling. SIRT4 is a tumor suppressor, in contrastto SIRT5 that promotes cell proliferation causing colorectal cancer; SIRT6 attenuates herpes virus associated with Kaposi's Sarcoma (KSHV) in immune compromised patients. Suppression of SIRT7 inhibits the growth of endometrial cancer cells. Conclusions: It is concluded that SIRT1, SIRT2 and SIRT4 are involved in the development of cancer, the suppression of SIRT5 and SIRT7 promotes the apoptosis of cancer cells and SIRT6 attenuates the replication of KSHV, in addition to the molecular pathology pathway of COVID-19 is associated with the inhibition of SIRT1 activity that may be related to inflammatory processes.

Introducción: Las proteínas desacetilasas dependientes del NAD+, se denominan Sirtuinas (SIRT). Objetivos: estudiar las sirtuinas involucradas en el cáncer, así como los estudios de inhibición de SIRT1 en pacientes con la enfermedad del coronavirus COVID-19. Fuente y selección de datos: Para ello se realizó una búsqueda en Medline, Scopus y WOS, donde se incluyeron estudios descriptivos de cada una de las funciones de las sirtuinas ajustado a las recientes investigaciones científicas. La inhibición de SIRT1 disminuye la citotoxicidad de las células T CD8 en pacientes con lupus eritematoso sistémico, siendo susceptibles a infecciones por SARS CoV-2. La SIRT2 se regula por la secreción de IL-4 por los eosinófilos y el aumento de SIRT2 incrementa la hiperplasia, en contraste la SIRT3 promueve la angiogénesis, induciendo la remodelación cardiaca. La SIRT4 es un supresor de tumores, en contraste con la SIRT5 que promueve la proliferación celular provocando el cáncer colorrectal; la SIRT6 atenúa al herpes virus asociado al Sarcoma de Kaposi (KSHV) en pacientes inmuno comprometidos. La supresión de SIRT7 inhibe el crecimiento de las células cancerígenas endometriales. Conclusiones: Se concluye que las SIRT1, SIRT2 y SIRT4 están involucradas en el desarrollo del cáncer, la supresión de SIRT5 y SIRT7 promueve la apoptosis de células cancerígenas y la SIRT6 atenúa la replicación de KSHV, además la vía de patología molecular de la COVID-19 está asociada a la inhibición de la actividad de SIRT1 que puede estar relacionada a procesos inflamatorios.

Betacoronavirus , Coronavirus Infections/metabolism , Neoplasms/metabolism , Pneumonia, Viral/metabolism , Sirtuin 1/antagonists & inhibitors , Biomarkers, Tumor/metabolism , COVID-19 , Histone Deacetylases/metabolism , Humans , Immunohistochemistry , Pandemics , SARS-CoV-2