Tryptophan Metabolites and Aryl Hydrocarbon Receptor in Severe Acute Respiratory Syndrome, Coronavirus-2 (SARS-CoV-2) Pathophysiology

Abstract

The metabolism of tryptophan is intimately associated with the differential regulation of diverse physiological processes, including in the regulation of responses to severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection that underpins the COVID-19 pandemic. Two important products of tryptophan metabolism, viz kynurenine and interleukin (IL)4-inducible1 (IL41)-driven indole 3 pyruvate (I3P), activate the aryl hydrocarbon receptor (AhR), thereby altering the nature of immune responses to SARS-CoV-2 infection. AhR activation dysregulates the initial pro-inflammatory cytokines production driven by neutrophils, macrophages, and mast cells, whilst AhR activation suppresses the endogenous antiviral responses of natural killer cells and CD8+ T cells. Such immune responses become further dysregulated by the increased and prolonged pro-inflammatory cytokine suppression of pineal melatonin production coupled to increased gut dysbiosis and gut permeability. The suppression of pineal melatonin and gut microbiome-derived butyrate, coupled to an increase in circulating lipopolysaccharide (LPS) further dysregulates the immune response. The AhR mediates its effects via alterations in the regulation of mitochondrial function in immune cells. The increased risk of severe/fatal SARS-CoV-2 infection by high risk conditions, such as elderly age, obesity, and diabetes are mediated by these conditions having expression levels of melatonin, AhR, butyrate, and LPS that are closer to those driven by SARS-CoV-2 infection. This has a number of future research and treatment implications, including the utilization of melatonin and nutraceuticals that inhibit the AhR, including the polyphenols, epigallocatechin gallate (EGCG), and resveratrol.

SARS-CoV2 Infection Alters Tryptophan Catabolism and Phospholipid Metabolism

“…No change was observed in the levels of kynurenines in our study. This is contrary to the currently available literature, which points towards lowered tryptophan serum levels on infection [36][37][38].…”

“…Essentially, there are two routes of tryptophan metabolism: Kynurenine pathway and the Indole-3-propionic acid (I3P) pathway. Both of these pathways result in activation of AhR leading to suppression of immune response (via exhaustion of NK cells and CD8+ T cells) [38]. Various studies have tested the kynurenine: tryptophan ratio to determine its effect on the progress of infection, but the activation of kynurenineindependent pathway has not been tested [36,37,45].…”

An untargeted metabolomic approach to identify antiviral defense mechanisms in memory leukocytes secreting in vitro IgG anti-SARS-Cov-2

“…IDO enzymes are activated by inflammatory cytokines (IFN-α,-β,-γ, TNF-α) and in particular interleukin-6 (IL-6) 15 . These changes in tryptophan metabolism, due to regulation of IDO enzymes, correlated with a greater increase of interleukin-6 (IL-6) levels 7 , induce a cytokine storm through aryl hydrocarbon receptor (AHR) 16 . The term ‘cytokine storm syndrome’ is perhaps one of the critical hallmarks of COVID-19 disease severity 17 .…”

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

“…It is therefore conceivable that melatonin administration may inhibit AhR and in this way drive part of its anti-inflammatory and immune-enhancing potential. Interestingly, regarding COVID-19, several nutraceuticals are functional antagonists of AhR and thereby their food intake has been postulated as a potential modulator of COVID-19 severity [106,110]. Then, the question that arises is: could melatonin be a relevant part of natural compounds capable of moderating the course of the disease in critically ill patients?…”