Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach

Abstract

The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients’ quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of SIRT1 in the pathogenesis of bronchial asthma. It also discusses the role of SIRT1 in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that SIRT1 is one of major contributors to cellular senescence. SIRT1 levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of SIRT1 in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and SIRT1. Therefore, targeting SIRT1 is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.

Renalase Challenges the Oxidative Stress and Fibroproliferative Response in COVID-19

“…Finally, SIRT1 activation remarkably inhibits oxidative stress [ 137 , 138 ] in vascular endothelial cells [ 139 ] that are heavily involved in the pathogenesis of the cytokine storm in COVID-19, knowing that hyperinflammation-induced uncontrolled oxidative stress results in substantial endothelial cell damage [ 8 – 10 , 12 , 13 ], capillary leak and edema formation, and subsequent ARDS worsening [ 140 ]. Given the various SIRTs activities, in the context of COVID-19, their supervision of the host cell's metabolism may be an equally required element in the regulation of the interaction of the viruses and humans [ 121 , 141 ].…”

The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections

“…Viruses depend on host-cell metabolism for energy, for production of viral components and genomes, as well as for organization of cellular compartments of replication, maturation and dissemination. As such, the control of the host cell’s metabolism by SIRTs appears to be an essential component that regulates the viral-host interaction [ 117 , 118 , 119 , 120 , 121 ]. Taking into account that SIRTs are molecular targets on human cells rather than on viruses, the development of resistance is less likely to occur.…”

“…It has been reported that, in some cases, SIRTs promote infection, while in other cases, SIRTs restrict infection [ 117 , 122 , 123 , 126 , 127 , 128 , 129 , 130 , 131 ]. Given the diverse activities of SIRTs as key regulators of transcription and metabolism, they can be considered as effective antiviral targets for the development of broad-spectrum antivirals, similar to the broad-spectrum antibiotics [ 119 , 120 , 121 ]. In addition, SIRTs can affect the replication of DNA and RNA viruses; hence, targeting through inhibition or activation can provide an effective antiviral therapeutic strategy.…”

“…In addition, the stress caused by viral replication often establishes a high NAD + -state that activates SIRTs [ 128 , 132 ]. Another approach can be based on the transcriptional functions of certain SIRTs that appear necessary for the regulation of viral gene expression [ 120 , 121 , 134 , 135 ]. Therefore, fine-tuning of SIRT regulation at the level of one enzyme or one function may be a valuable way forward to take advantage of SIRT defense properties [ 120 , 135 , 136 ].…”

“…The life-cycle of a virus involves the biosynthesis of viral components that depend on host-cell metabolic conditions. Therefore, the regulation of the host cell’s metabolism is a key function of the viral-host interaction [ 117 , 118 , 119 , 120 , 121 ]. One of the core roles of SIRT1 and SIRT2 is to control metabolism and gene expression through post-translational modification of several regulatory proteins in the host cell as well as in virus [ 19 , 41 ].…”