👤 Sten Skogmar

The role of ribonucleases in tuberculosis among people with human immunodeficiency virus (HIV; PWH) is unknown. We explored ribonuclease activity in plasma from PWH with and without tuberculosis. Participants were identified from a cohort of treatment-naive PWH in Ethiopia who had been classified for tuberculosis disease (HIV positive [HIV+]/tuberculosis positive [tuberculosis+] or HIV+/tuberculosis negative [tuberculosis-]). Ribonuclease activity in plasma was investigated by quantification of synthetic spike-in RNAs using sequencing and quantitative polymerase chain reaction and by a specific ribonuclease activity assay. Quantification of ribonuclease 1, 2, 3, 6, 7, and T2 proteins was performed by enzyme-linked immunosorbent assay. Ribonuclease activity and protein concentrations were correlated with markers of tuberculosis and HIV disease severity and with concentrations of inflammatory mediators. Ribonuclease activity was significantly higher in plasma of HIV+/tuberculosis+ (n = 51) compared with HIV+/tuberculosis- (n = 78), causing reduced stability of synthetic spike-in RNAs. Concentrations of ribonucleases 2, 3, and T2 were also significantly increased in HIV+/tuberculosis+ compared with HIV+/tuberculosis-. Ribonuclease activity was correlated with HIV viral load, and inversely correlated with CD4 cell count, mid-upper arm circumference, and body mass index. Moreover, ribonuclease activity was correlated with concentrations of interleukin 27, procalcitonin and the kynurenine-tryptophan ratio. PWH with tuberculosis disease have elevated plasma ribonuclease activity, which is also associated with HIV disease severity and systemic inflammation. Show less

: The aim of this study was to assess the performance of kynurenine/tryptophan ratio for tuberculosis (TB) case-finding among antiretroviral therapy (ART)-naive people with HIV (PWH), and to investigate other factors associated with kynurenine/tryptophan ratio in this population. : A nested case--control study based on a cohort of 812 ambulatory PWH in the Oromia region, Ethiopia. : At enrolment, all participants submitted sputum samples for bacteriological TB investigations. Concentrations of kynurenine and tryptophan in plasma were quantified using liquid chromatography-mass spectrometry. Receiver operator characteristic curves were constructed to assess diagnostic performance (area under the curve; AUC) for kynurenine, tryptophan, and kynurenine/tryptophan ratio. Sensitivity, specificity, and predictive values were calculated. Kynurenine/tryptophan ratios were correlated to plasma levels of nine inflammation mediators, plasma HIV RNA levels, CD4 + cell count, BMI, and mid-upper arm circumference (MUAC). : We included 124 individuals with HIV-TB coinfection (HIV+/TB+) and 125 with HIV mono-infection (HIV+/TB-). Tryptophan levels were lower in HIV+/TB+ than in HIV+/TB- (median 19.5 vs. 29.8 μmol/l, P  < 0.01), while kynurenine levels were similar between these groups (median 2.95 vs. 2.94 μmol/l, P  = 0.62). Median kynurenine/tryptophan ratio was 0.15 in HIV+/TB+, significantly higher compared with HIV+/TB- (0.11; P  < 0.01), with AUC 0.70 for TB detection. Kynurenine/tryptophan ratio was positively correlated to plasma HIV RNA levels, IP-10, IL-18, and IL-27, and negatively correlated to CD4 + cell count, BMI, and MUAC (all P  < 0.01). : Among ART-naive PWH, kynurenine/tryptophan ratio has modest potential for TB discrimination, limiting its utility for TB case-finding in this population. Show less