Melatonin Inhibits Dengue Virus Infection via the Sirtuin 1-Mediated Interferon Pathway

Abstract

Dengue virus (DENV) is the causative pathogen in the life-threatening dengue hemorrhagic fever and dengue shock syndrome. DENV is transmitted to humans via the bite of an infected Aedes mosquito. Approximately 100 million people are infected annually worldwide, and most of those live in tropical and subtropical areas. There is still no effective drug or vaccine for treatment of DENV infection. In this study, we set forth to investigate the effect of melatonin, which is a natural hormone with multiple pharmacological functions, against DENV infection. Treatment with subtoxic doses of melatonin dose-dependently inhibited DENV production. Cross-protection across serotypes and various cell types was also observed. Time-of-addition assay suggested that melatonin exerts its influence during the post-entry step of viral infection. The antiviral activity of melatonin partly originates from activation of the sirtuin pathway since co-treatment with melatonin and the sirtuin 1 (SIRT1) inhibitor reversed the effect of melatonin treatment alone. Moreover, melatonin could modulate the transcription of antiviral genes that aid in suppression of DENV production. This antiviral mechanism of melatonin suggests a possible new strategy for treating DENV infection.

INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation

“…Hence, a potent antiviral approach is the restoration of the host IFN response to block the infection early. This can be achieved by directly targeting viral IFN antagonists [28,[60][61][62][63][64][65] and/or enhancing the cellular innate immunity [66][67][68][69]. NS4B is a well-investigated target for flaviviral therapy [70].…”

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

“…Clinically, melatonin treatment reduces the severity of SARS-CoV-2 infections in terms of lowering the seriousness of symptoms, decreasing the need for hospitalization (which simultaneously helps control health care exhaustion), reducing the duration of hospital stay when this is necessary, eliminating the need for mechanical intubation, and lessening the death rate [4,11]. Even prior to the identification of the current COVID-19 pandemic, melatonin was shown effective in reducing oxidative damage and lowering the inflammatory burden in other viral diseases [97][98][99][100][101], including those caused by other coronaviruses [102], and it has been classified as a potential pan-antiviral agent, although it is not viricidal.…”

A Review of the Potential Effects of Melatonin in Compromised Mitochondrial Redox Activities in Elderly Patients With COVID-19

“…Further, the effects of melatonin seem to be closely related to the upregulation of SIRT1. Melatonin also interferes with mTOR and Notch signaling and reduces the expression of pro-inflammatory lncRNA-CCL2 ( 218 ). Compared with younger adults, the elderly are more likely to contract severe COVID-19, and the degree of inflammation and aberrant immune response is closely related to the mitochondrial function.…”

“…SIRT1 induced by melatonin can enhance virus-mediated MAVS activation ( 218 ). Through mitochondrial membrane receptors, melatonin induces the nuclear translocation of the transcription factor retinoid-related orphan receptor alpha (RORα).…”