LAUSR

Dear Prof. Gendelman: Melatonin MLT) or N-acetyl-5-methoxy-tryptamine is an indoleamine synthesized and immediately secreted in the blood during the night darkness hours by the pineal gland. Circulating MLT has the fundamental role of synchronizing the organism in the photoperiod (Claustrat and Leston 2015). MLTmay, however, be synthesized in many other organs and cell types including primary and secondary lymphoid organs as well as circulating immunocompetent cells. Extra pineal MLT does not contribute to the circulating pool and conveys only autocrine or paracrine signals (Maestroni 2001). Being an ancient molecule, MLT developed several pleiotropic effects. Probably the most primordial of these involve the direct interaction of MLT with other molecules as in the case of its well-known powerful antioxidant action. Then during evolution, MLT became gradually a classical hormone acting through specific receptors. In mammals there are two type of membrane receptors, MT1 (MTNR1A, in humans) and MT2 (MTNR1B in humans). Both MT1 and MT2 may be found in almost all tissues as heterotrimeric Gi/ Go and Gq/11 proteincoupled receptors interacting with downstream messengers such as adenylyl cyclase, phospholipase A2 and phospholipase C, decreasing cAMP and cGMP production and/or increasing diacylglycerol and IP3 formation. Furthermore, MLT might interact at the nuclear level with retinoid orphan receptors/ retinoid Z receptors (Jockers et al. 2016). One of the most interesting property ofMLT is its ability to modulate the immune response. The first evidence that MLT could increase the IgG antibody response and counteract the immunosuppressive effect of corticosteroid and/or acute stress was provided by myself some decades ago (Maestroni et al. 1987; Maestroni 2001). The immunoregulatory role of MLT is today widely accepted. It has been proposed that MLT may act as an immune buffer, stimulating the immune response under basal or immunosuppressive conditions or exerting an anti-inflammatory action in the presence of exaggerated immune responses (Carrillo-Vico et al. 2013; Mortezaee et al. 2019). This double-edged effect may depend on the ability of MLT to interfere with T cell differentiation and control the balance between pathogenic and regulatory T cells. MLT can promote the differentiation of type 1 regulatory T cells via extracellular signal regulated kinase 1/2 (Erk1/2) and retinoic acid-related orphan receptor-α (ROR-α) and suppress the differentiation of Th17 cells via the inhibition of ROR-γt and ROR-α expression through NFIL3. In relation to viral diseases, MLT proved to counteract the infection in variety of models (Maestroni 2001) and recently it has been suggested to be of potential therapeutic value in reducing the severity of Covid-19 (Shneider et al. 2020). As a matter of facts, Covid-19 may be remarkably severe in elderly males, i.e. in a population in which plasma levels of MLT may be particularly low (Touitou et al. 1985). As far as it concerns vaccines, several studies demonstrated that exogenous MLT may act as an adjuvant enhancing both CD8 + T cell response in cancer vaccines (Moreno et al. 2018; BaghdamRahimi et al. 2018) and humoral responses against a variety of pathogens (Regodon et al. 2005). Recently it has been demonstrated in an animal model that melatonin enhances the immune response to a vaccine by increasing peripheral blood CD4 + T cells and IgGexpressing B cells (Ramoset al. 2008). This finding is particularly interesting as a recent study in Covid-19 convalescent patients, found a vigorous CD4 T cell responses to spike protein, the main target of most vaccines, and that such a response correlated with the level of the anti-SARS-CoV-2 IgG and IgA titers (Grifoni et al. 2020). However, in some patients the immune response might not be sufficient as relapses have already been reported, so it appears that long-term natural immunity might not prevent the current and future outbreaks (Papachristodoulou et al. 2020). Therefore, the development of an effective vaccine is commanding to control the disease. Most interesting, critically ill * Georges Maestroni [email protected]