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.

中文翻译：

---

褪黑激素：在流感、Covid-19 和其他病毒感染中的作用。


人们越来越认识到，松果体和全身褪黑素能途径的调节可能是病毒驱动细胞变化的一个重要方面，而细胞变化是其控制细胞功能的基础。我们回顾了褪黑素通路在病毒感染中的作用，重点关注流感和 covid-19 感染。病毒或预先存在的松果体褪黑激素抑制会抑制中性粒细胞的吸引力，从而导致最初的“细胞因子风暴”以及其他免疫细胞的调节。褪黑激素诱导昼夜节律基因 Bmal1，该基因可抑制丙酮酸脱氢酶复合物 (PDC)，从而对抗病毒对 Bmal1/PDC 的抑制。 PDC 驱动线粒体将丙酮酸转化为乙酰辅酶 A (乙酰辅酶 A)，从而增加三羧酸循环、氧化磷酸化和 ATP 产生。松果体褪黑激素抑制会减弱这种作用，从而阻止线粒体代谢的昼夜节律“重置”。这在免疫细胞中尤其重要，其中代谢从糖酵解转变为氧化磷酸化，将细胞从反应性表型转变为静止表型。乙酰辅酶A是芳烷基胺N-乙酰转移酶必需的共底物，为血清素提供乙酰基，从而启动褪黑激素途径。因此，松果体褪黑激素调节线粒体褪黑激素和免疫细胞表型。因此，病毒和细胞因子风暴驱动的松果体和线粒体褪黑激素通路的控制可以调节免疫反应。病毒和细胞因子风暴驱动的变化也会增加肠道通透性和生态失调，从而抑制短链脂肪酸、丁酸盐的水平，并增加循环脂多糖（LPS）。 丁酸盐和脂多糖的改变可以通过影响褪黑激素途径来促进病毒复制和宿主症状的严重程度。关注免疫调节剂对治疗 covid-19 和其他病毒感染具有重要意义。