5-Hydroxytryptophan, a major product of tryptophan degradation, is essential for optimal replication of human parainfluenza virus

- Tryptophan, the rarest amino acid in the cell, is degraded via two major pathways.
- The kynurenine pathway is initiated by indolamine 2,3-dioxygenase (IDO).
- An alternative pathway produces 5-hydroxytryptophan, and we find it as proviral.
- Induction of IDO deprives the cell of 5-hydroxytryptophan and reduces virus growth.
- This may explain the antiviral role of IDO, an interferon-stimulated gene (ISG).

Interferon (IFN) exerts its antiviral effect by inducing a large family of cellular genes, named interferon (IFN)-stimulated genes (ISGs). An intriguing member of this family is indoleamine 2,3-dioxygenase (IDO), which catalyzes the first and rate-limiting step of the main branch of tryptophan (Trp) degradation, the kynurenine pathway. We recently showed that IDO strongly inhibits human parainfluenza virus type 3 (PIV3), a significant respiratory pathogen. Here, we show that 5-hydoxytryptophan (5-HTP), the first product of an alternative branch of Trp degradation and a serotonin precursor, is essential to protect virus growth against IDO in cell culture. We also show that the apparent antiviral effect of IDO on PIV3 is not due to the generation of the kynurenine pathway metabolites, but rather due to the depletion of intracellular Trp by IDO, as a result of which this rare amino acid becomes unavailable for the alternative, proviral 5-HTP pathway.