Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests

Abstract

l-Tryptophan (l-Trp) is an essential amino acid that possesses diverse metabolic, neurological, and immunological roles spanning from the synthesis of proteins, neurotransmitter serotonin, and neurohormone melatonin, to its degradation into immunosuppressive catabolites by indoleamine-2, 3-dioxygenase (IDO) in the kynurenine pathway (KP). Trp catabolites, by activating aryl hydrocarbon receptor (AhR), play an important role in antimicrobial defense and immune regulation. IDO/AhR acts as a double-edged sword by both depleting l-Trp to starve the invaders and by contributing to the state of immunosuppression with microorganisms that were not cleared during acute infection. Pathogens experiencing Trp deprivation by IDO-mediated degradation include certain bacteria, parasites, and less likely viruses. However, chronic viral infections highjack the host immune response to create a state of disease tolerance via kynurenine catabolites. This review covers the latest data involving chronic viral infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes, and cytomegalovirus (CMV) and their cellular interplay with Trp catabolites. Strategies developed by viruses to escape immune control also represent new avenues for therapeutic interventions based on Trp metabolism.

Keywords: AhR; CMV; HIV; IDO; herpes; tryptophan metabolism; viral hepatitis.

Figure 1

Schematic representation of key enzymes and metabolites in the Trp/Kyn catabolic pathway, depicting frequent pathogens and the tissues/organs involved. Dietary Trp can be catabolized in the digestive tract by AhR-IDO-IL22 axis or by immunosuppressive Kyn pathway involving multiple enzymes, metabolites, and body organs. TDO, IDO-1, and IDO-2 are the first enzymes implicated in the Trp catabolism involving gut, immune cells, and liver. In muscles, exercise leads to the depletion of Kyn by inducing its catabolism into the nonbrain penetrating kynurenic acid. Overproduction of Kyn and its ligation to AhR leads to the induction of immunosuppressive cells. Trp metabolites like serotonin, Quin, and kynurenic acid have important implications in the brain function and mood disorders. NAD, an important cellular cofactor, is also produced by the liver during Trp catabolism. The list of microbial pathogens for which cell growth is reduced with Trp depletion or contributes to a state of immunosuppression/tolerance via KP is also depicted.

Figure 2

Schematic representation of Trp metabolism and immune cell interactions in health and infection.