Melatonin: Roles in influenza, Covid-19, and other viral infections

Abstract

There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.

Keywords: aryl hydrocarbon receptor; covid-19; immune; influenza; melatonin; metabolism; mitochondria; sirtuin; treatment; viral infection.

FIGURE 1

The cytokine storm and stress can increase gut dysbiosis/permeability, further contributing to cytokine induced IDO and TDO, leading to kynurenine and kynurenic acid, which activate the AhR to increase CYP1B1 and regulate the NAS/Melatonin ratio. Other factors, including CYP2C19, mGluR5, P2Y1, and O‐demethylation can also regulate the NAS/melatonin ratio. The miRNAs, miR‐7, miR‐375, and miR‐451 are increased following many viral infections, thereby suppressing 14‐3‐3 and the stabilization of AANAT, leading to melatonergic pathway inhibition. The suppression of melatonin, including from an increase in the NAS/melatonin ratio, attenuates melatonin's induction of Bmal1 and therefore the circadian regulation of mitochondria. Bmal1 induces PDC, leading to an increase in OXPHOS, the TCA cycle and the acetyl‐CoA that is a necessary co‐substrate for AANAT and melatonergic pathway activation. The decrease in pineal and mitochondrial melatonin contributes to an increase in the replication and severity of many viral infections. The arrows indicate “stimulation”, with a crossed‐line indicating “inhibitory”