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.

Keywords: COVID-19; SARS-CoV-2; aryl hydrocarbon receptor; severe acute respiratory syndrome; tryptophan.

Figure 1

Scheme showing how the SARS-CoV-2 virus, and pre-existent high-risk medical conditions, shift tryptophan metabolism to increase AhR ligands. The activation of the AhR alters the nature of the initial ‘cytokine storm’ and suppresses the endogenous antiviral responses of NK cells and CD8+ T cells, leading to a prolonged activation of macrophages, neutrophils, and mast cells, as evident in severe SARS-CoV-2 infection. The driving to tryptophan to kynurenine and I3P, along with the elevated pro-inflammatory cytokines of the ‘cytokine storm’, also suppresses pineal melatonin production and therefore the induction of the α7nAChR by melatonin, thereby contributing lost vagal dampening of immune activity and raising sympathetic nervous system activation. The elevation in pro-inflammatory cytokines also increases gut dysbiosis/permeability, leading to a decrease in butyrate and raising LPS levels, further contributing to metabolic dysregulation of patterned immune responses to SARS-CoV-2 infection. A number of readily available nutraceuticals, such as resveratrol, EGCG, folate, vitamin B12, and curcumin, by AhR inhibition, may act to modulate how many processes influence SARS-CoV-2 pathophysiology.