Immune mediators in people with HIV and tuberculosis

Sammanfattning: Tuberculosis (TB) is the most common cause of death among people with HIV (PWH). PWH often have atypical clinical manifestations of TB, and TB disease can therefore be missed. Better screening markers could identify individuals with high likelihood of TB disease. Furthermore, the mechanisms underlying the immunopathogenesis of TB disease in PWH remain incompletely understood.This thesis is based on a cohort of 812 treatment-naïve PWH recruited in Ethiopia, who were investigated with bacteriological methods for TB regardless of symptoms. TB disease was diagnosed in 137 (16.9%, HIV+/TB+), and the remainder were classified as HIV+/TB-. In the first paper, we investigated nine markers of systemic inflammation in plasma in a subset of 260 individuals. The levels of eight of these markers were significantly increased in HIV+/TB+. Combinations were assessed with logistic multivariate models, and a combined model of C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR) was found to have superior discriminatory capacity to any of the markers alone. In the subset of individuals with CD4 count <200 cells/mm3, this combination achieved the desired performance (>90% sensitivity and >70% specificity) of a screening marker for TB in PWH. In the second paper, we investigated the ratio between the amino acid tryptophan and its metabolite kynurenine (KT ratio) in plasma from 249 individuals. Although the KT ratio was significantly increased in HIV+/TB+, it did not show discriminatory capacity to a degree that would be clinically useful. In the third paper, we investigated expression profiles of microRNA (miRNA) and small nucleolar RNA (snoRNA) in whole blood of individuals with TB disease, with and without HIV, and uninfected controls (total n=40). We found 218 miRNAs, several of which have known roles in the TB immune response, to be differentially expressed between HIV+/TB+ and HIV-/TB+. We also found 103 snoRNA to be significantly downregulated in people with TB. These changes were partially reversed with treatment for TB and HIV.In the fourth paper, we investigated plasma ribonuclease activity in 129 PWH with and without TB. Using three different techniques, we identified increased ribonuclease activity in HIV+/TB+ individuals. We subsequently identified three different ribonuclease proteins, ribonucleases 2, 3 and T2, that were also increased in HIV+/TB+, with varying degrees of correlation to total ribonuclease activity. In summary, this thesis includes studies on different types of blood-based biomarkers of TB disease in PWH, identifying promising performance of a combination of CRP and suPAR. Ways in which HIV and TB interact and alter immune mediators have also been investigated, and the findings point towards involvement of miRNA, snoRNA and ribonucleases.