Fig. 6: Virus-induced HMRD of tryptophan metabolism/neuro-cognitive implications.
The SARS-CoV-2-induced HMR affects tryptophan metabolism by lowering the levels of tryptophan, serotonin, and indole-pyruvate, while elevating the levels of kynurenine, kynurenic acid, picolinic acid, and nicotinic acid51,424. After conversion to kynurenine, the tryptophan catabolism divides into different branches, leading to the formation of 3-OH-kynurenine, anthranilic acid or kynurenic acid. The 3-OH-kynurenine catabolism further leads to the generation of picolinic acid, quinolinic acid, and nicotinamide. The neuroprotective kynurenic acid is present mainly in astrocytes, neurotoxic 3-OH-kynurenine and excitotoxic quinolinic acid are found in microglial cells. Besides directly targeting neurotransmitter receptors, the tryptophan metabolites, in particular 3-OH-kynurenine and 3-OH-anthranilic acid, are redox active that impact brain physiology789. The modulation of the tryptophan-kynurenine pathway is an indicator for a coherent metabolic shift790. The tryptophan-nicotinamide pathway is associated with inflammatory signals and coordinator of cell metabolism in SARS-CoV-2 infection791. The broader virulence spectrum of SARS-CoV-2 with ability to cross the BBB and inflict a plethora of neuropathological manifestations by HMRD in host brain metabolism has been elucidated as ‘Neuro-COVID-19’171.
