Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia

Abstract

Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome’s evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.

Treatment of 95 post-Covid patients with SSRIs

“…28 Because the metabolites kynurenine and kynurenine acid are agonists of the AHR receptor, there is a 'runaway positive feedback loop' producing more and more metabolites. 28,[30][31][32]…”

“…The KP is stimulated by inflammation and in PCS it is found overactive. [26][27][28]30,32 [Figure 6 here]…”

“…Research shows that the amount of tryptophan in blood is decreased in PCS patients. [30][31][32] Tryptophan deficiency is probably already present during the infection with Covid-19, because Covid-19 attaches with its spike proteins to the Angiotensin Converting Enzyme (ACE2) receptors in the intestines, while tryptophan also uses the same receptor to be absorbed from the intestines. 54 There is a significant relationship between the level of metabolites in blood and the severity of cognitive impairment in PCS, 28 (p < 0.001).…”

“…1,20,55,56 Kynurenic acid is a nicotine-receptor antagonist and a glutaminergic-receptor antagonist. 28,30,32 Quinolinic acid blocks the glutaminergic receptor. 28 When we want to intervene: the kynurenine pathway can be inhibited in various ways and the serotonin pathway can be stimulated in various ways.…”

A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation

“…50,51 In this context, our data suggest that a KD may improve patient health with reduced risk of hospitalization and long covid. 52,53 On the contrary, a diet rich in carbohydrates may exacerbate the inflammatory response during infection.…”