The tryptophan(trp)-kynurenine(kyn)-nicotinamide pathway is of interest in Tuberculosis (TB) pathogenesis and biomarker development. The pathway is catalysed in macrophages by the host enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1), encoded by the IDO-1 gene. IDO-1 activity is induced by interferon gamma and is elevated in people living with HIV (PLWH). We conducted a nested case-control study to characterise the peripheral blood kyn/trp ratio in patients with active TB and their recently exposed household contacts. Data were analysed descriptively and by logistic regression.
Using an ELISA to quantify kyn and tryp, and real-time PCR for IDO-1 gene expression, we noted that household contacts had higher kyn/trp values (median 0.09 [IQR: 0.06-0.12]) than controls, signifying that elevations in the kyn/trp ratio may reflect incident TB exposure. In HIV-uninfected individuals, we found that the kyn/trp ratio and IDO-1 gene expression were significantly higher in individuals with TB disease than in household contacts (median kyn/trp 0.12 [IQR: 0.09-0.19], adjusted p = 0.0038; median IDO Δ Ct 11.58 [IQR = 10.79 – 13.53] vs 8.48 [IQR = 7.33 – 9.74], adjusted p = 0.0010). In contrast, no significant differences in kyn/trp or IDO-1 gene expression were found between cases and household contacts in PLWH. There was a significant association between indeterminate tests for latent TB infection (QuantiFERON TB Gold Plus) with high kyn/trp ratios (adjusted p = 0.0358). By six months post enrolment, kyn/trp values of both cases and household contacts had fallen to levels of healthy individuals. Higher kyn/trp ratio (OR: 3.552, 95% CI: 1.405-8.977) and higher IDO-1 gene expression (ΔCt OR: 2.362, 95% CI: 1.452-3.841) were associated with elevated odds of TB disease.
These findings suggest that the kyn/trp pathway warrants scrutiny for development of a quantitative, blood-based biomarker for recent TB exposure and, in HIV-uninfected individuals, for screening for active TB disease.