Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Abstract

Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen’s spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host’s tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.

Maternal Serum Melatonin Increases During Pregnancy and Falls Immediately After Delivery Implicating the Placenta as a Major Source of Melatonin

“…However sources from the mother and fetus as well as the placenta may also contribute. Given the anti-inflammatory effects of melatonin it is interesting to speculate that the high melatonin levels may be involved in the resistance of pregnant women to COVID-19 ( 23 ). Unlike in other studies ( 6 , 8 ), the same patients were sampled throughout pregnancy which both increased the power of the study and minimized the contribution of inter-individual variation.…”

Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies

“…Although some improvements of sleep duration or sleep quality can be obtained with conventional doses of melatonin, such as 2 or 3 mg, the aim of complete sleep maintenance has practically never been reached [ 60 , 122 , 123 , 124 ]. This statement is also valid for all synthetic melatonergic agonists, even though some of them such as ramelteon were somewhat more efficient in this regard than melatonin [ 60 , 69 , 125 ]. Higher doses such as 50 or 100 mg melatonin have been suggested for more efficient support of sleep maintenance [ 97 ], but these have not yet been applied in sufficiently large clinical studies.…”

“…This has been convincingly shown in freely moving rats, when melatonin was continually infused during the day to attain night-time levels and its distribution was followed by a [ 3 H]–labeled fraction [ 61 ]. Of note, mitochondrial melatonin formation has gained recent actuality concerning the hijacking of mitochondria by viruses including SARS-CoV2 [ 69 ].…”

Melatonin Alleviates the Suppressive Effect of Hypoxanthine on Oocyte Nuclear Maturation and Restores Meiosis via the Melatonin Receptor 1 (MT1)-Mediated Pathway

“…MT1 KO may affect the production of LH by affecting mitochondrial function since melatonin and LH are both synthesized in mitochondria. Second, MT1 KO significantly downregulated the expression of genes related to progesterone synthesis ( Cyp11a 1), cholesterol biosynthesis ( Insig1 ), and feedback ( Lhcgr , Prlr , and Atg7 ) in oocytes, and all these genes were associated with LH synthesis and located in the mitochondria ( Tan and Hardeland, 2020 ). In the current study, although we did not detect the LH level in the MT1 KO mice, the results supported this speculation.…”