title: Distinct Patterns of Tryptophan Maintenance in Tissues during Kynurenine Pathway Activation in Simian Immunodeficiency Virus-Infected Macaques.
abstract: Induction of the kynurenine pathway (KP) of tryptophan (TRP) catabolism has been proposed to contribute to T cell dysfunction during human/simian immunodeficiency virus (SIV) infectionviadepletion of local TRP levels and production of immunomodulatory KP metabolites. However, while changes in TRP and KP metabolites have been observed in plasma, their levels in lymphoid tissues and levels of enzymes downstream of indoleamine 2,3-dioxygenase (IDO1) have been relatively unexplored. We used our SIV-infected pigtailed macaque model to analyze longitudinal changes in KP metabolites and enzymes by gas chromatography/mass spectrometry and NanoString nCounter gene expression analysis, respectively, in spleen and blood compared to changes previously established in brain and CSF. We found that TRP levels were remarkably stable in tissue sites despite robust depletion in the circulating plasma and CSF. We also demonstrated that intracellular TRP reserves were maintained in cultured cells even in the presence of depleted extracellular TRP levels. Kynurenine (KYN), 3-hydroxykynurenine, quinolinic acid, and the KP enzymes all displayed highly divergent patterns in the sites examined, thoughIDO1expression always correlated with local KYN/TRP ratios. Finally, we demonstrated by fluorescence-activated cell sorting that myeloid dendritic cells and cells of monocytic lineage were the highest producers ofIDO1in chronically infected spleens. Overall, our study reveals insights into the tissue-specific regulation of KP enzymes and metabolites and, in particular, highlights the multiple mechanisms by which cells and tissues seek to prevent TRP starvation during inflammation.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Drewes
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Croteau
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Shirk
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Engle
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Zink
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Graham
keywords: HIV; IDO1; SIV; immunosuppression; kynurenine; spleen; tryptophan