Potential utility of melatonin in deadly infectious diseases related to the overreaction of innate immune response and destructive inflammation: focus on COVID-19

Abstract

The high mortality
 of deadly virus infectious diseases including SARS, MERS, COVID-19, and avian
 flu is often caused by the uncontrolled innate immune response and destructive
 inflammation. The majority of viral diseases are self-limiting under the help
 of the activated adaptive immune system. This activity is cell proliferation
 dependent and thus, it requires several weeks to develop. Patients are
 vulnerable and mortality usually occurs during this window period. To control the
 innate immune response and reduce the inflammation during this period will
 increase the tolerance of patients and lowers the mortality in the deadly virus
 infection. Melatonin is a molecule that displays respective properties, since
 it downregulates the overreaction of the innate immune response and
 overshooting inflammation, but also promotes the adaptive immune activity. Many
 studies have reported the beneficial effects of melatonin on deadly virus
 infections in different animal models and its therapeutic efficacy in septic
 shock patients. Furthermore, melatonin has a great safety margin without
 serious adverse effects. We suggest the use of melatonin as an adjunctive or
 even regular therapy for deadly viral diseases, especially if no efficient
 direct anti-viral treatment is available.

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

“…For example, a general antiviral requirement for influenza and covid-19 would be for a treatment that limits the initial innate immune-associated "cytokine storm" where evident, while also acting to increase the efficacy of the adaptive immune response. 2 However, for the Ebola virus, such initial dampening of the innate immune response is not so clinically relevant. Allowing for such variability in virus effects, melatonin has emerged as a top candidate for protection against an array of different viruses, including the coronavirus.…”

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

“…Melatonin is a naturally occurring molecule assumed to be present in every species [ 19 ]. Due to its antioxidant, anti-inflammatory, as well as other properties [ 20 , 21 , 22 , 23 , 24 , 25 ], it has been speculated to be a promising molecule for treating COVID-19 patients [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and also other deadly viral infectious diseases [ 48 , 49 , 50 , 51 ]. A small scale clinical trial has also shown promising results [ 52 ].…”

“…A small scale clinical trial has also shown promising results [ 52 ]. The major activities of melatonin are not directed towards the virus per se and, thus, it does not kill the virus, but rather buffers the immune response of the host and increases the tolerance of the host to the virus infection [ 26 ]. Additional assumptions that melatonin may help to block virus entry into cells have also been hypothesized [ 28 , 42 ].…”

“…Regardless of this possibility, melatonin seems to reduce the severity and mortality for COVID-19. Its efficacy in other deadly viral diseases has been recently summarized [ 26 ]. We know that virus infections are self-limiting diseases if the patients have sufficient time for developing antibodies before the host organism has lost control.…”

“…Most of the time, disease severity or mortality of the victim are not caused by direct viral cytotoxicity, but result from the manifestation of the host’s immune response. Sometimes, this is referred to as the cytokine storm, which unproportionally magnifies the signal of virus invasion and results in destructive inflammatory responses [ 26 ]. Thus, downregulation of the innate immune response, as in the case of bats, is a feasible strategy to increase the tolerance of the host.…”