Differential Expression Patterns of Indoleamine 2,3-Dioxygenase 1 and Other Tryptophan and Arginine Catabolic Pathway Genes in Dengue Correlate with Clinical Severity-Pilot Study Results.

Abstract

The kynurenine pathway of tryptophan catabolism can modulate inflammatory responses inducing immunotolerance or immunosuppressive effects. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in this pathway. Early aberrant inflammation is implicated in severe dengue, and herein we investigate and characterize the expression of IDO pathway genes in severe dengue patients. We use a SyBR green-based qPCR to evaluate the leukocyte expression levels of IDO1, IDO2, AhR, TGF-β, ARG1, IFNγ, and IFNα in a dengue patient cohort (n = 51). Twenty-two cases were identified as severe dengue using the WHO case classification (2009) criteria. Principal component analysis (PCA) was employed to examine the relationships of gene expression profiles with disease severity and laboratory markers of clinical severity. We find that two principal components describe most of the variance (65.3%) in the expression patterns of the cohort. Reduced expression of IDO1, TGF-β, and AhR, represented by low Component 2 scores, was significantly associated with disease severity, thrombocytopenia, and leukopenia. Higher expression levels of IDO2, IFNγ, and IFNα positively correlated with Component 1 scores, and were significantly associated with elevated ALT (p = 0.018) and AST (p = 0.017) enzymes. Our results suggest that profiling the baseline expression patterns of the IDO pathway genes may aid in the identification of dengue patients most at risk of severe disease.