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.

Protein Malnutrition Alters Tryptophan and Angiotensin-Converting Enzyme 2 Homeostasis and Adaptive Immune Responses in Human Rotavirus-Infected Gnotobiotic Pigs with Human Infant Fecal Microbiota Transplant

“…Tryptophan also decreases during chronic viral infection with hepatitis B and C, HIV, herpesvirus, and cytomegalovirus (reviewed in reference 39). During these instances where virus is not cleared, IDO is persistently activated and may serve to balance tissue damage by inhibiting antiviral T cell responses and enhancing Tregs, leading to removal of the virus from immune surveillance, creating tolerance (39).…”

“…Low plasma tryptophan is a predictor of poorer subsequent growth in boys and is associated with biomarkers of barrier disruption and intestinal and systemic inflammation in children of both genders (38). Tryptophan catabolism via the indoleamine 2,3-dioxygenase (IDO) pathway has immunoregulatory effects, and its depletion has been well studied in the context of chronic infections (39); however, the interrelationship between tryptophan and the adaptive immune response to RV and other acute infections is less clear, particularly in the context of host protein malnutrition.…”

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…However, this study did not measure serotonin. In a state of infection, the catabolism of TRP is activated [12]. Given these results from mostly animal studies, there is interest in a larger clinical study investigating how adaptations in the TRP/5-HT pathway interact with severity and outcome in patients with a well-defined infection.…”

Hepatitis C virus drives the pathogenesis of hepatocellular carcinoma: from immune evasion to carcinogenesis

“…15 Trp catabolites were shown to have an important balancing role in both antimicrobial defence and immune regulation, at least in part through Kyn-mediated AhR activation. 16 Therefore, IDO/TDO-mediated AhR activation generates conflicting effects by (a) depleting L -Trp to starve the invading pathogens and (b) contributing to downregulation of the inflammatory response against microorganisms that survived the acute response. 16 IDO-mediated degradation results in Trp deprivation, affecting various pathogens including certain bacteria, parasites and occasionally viruses.…”