Biomarkers for tuberculosis in the context of HIV/AIDS in Ethiopia

Abstract

Tuberculosis remains to be one of the severe infectious diseases, especially in developing countries. Universal and specific biomarkers for TB could accelerate the development of novel diagnostics and therapies for TB, which are urgently needed to control the epidemic effectively. In the studies included in this thesis, several candidate biomarkers for latent and active TB have been identified. Our study design for testing novel Mtb antigens, revealed combined measurement of specific cytokines (IFN-γ, TNF-α, IL-6 and IL-10) in response to a subset of antigens (Rv0081, Rv2629, Rv1733c, Rv2006) could be a promising path to develop immunodiagnostics. We also presented data, which suggest combined measurement of IFN-γ IFN F γ-17, and IP-10 in response to ESAT-6/CFP-10 could be useful immune markers for the diagnosis LTBI; IL-2 and IP-10 for the diagnosis of active TB; and IFN-γ, IL-17, MIP-1α, and IL-10 to discriminate latent and active TB. In addition, FCGR1A, TIMP-2, IL-7R and CD8A whole blood genes could be useful to classify active TB in HIV patients We showed that IL-2, IFN-γ and IP-10 in response ESAT-6/CFP-10; and the leukocyte subsets (TLC, WBC, neutrophil) to be useful markers to monitor treatment in HIV negative TB patients. Similarly, IL-10 and MIP-1α in response to ESAT-6/CFP-10 may assist to monitor TB treatment and HAART. In summary, whereas we feel that these identified biomarkers will have significant contribution towards TB control in the future, the effects of other potential confounding factors including endemic infections such as malaria and helminthes, granulomatous disease, host genetics, and Mtb lineages need to be addressed before these new biomarkers are moving to clinical practices. Thus, we propose context-dependent validation studies by comparing findings from prospective cohorts from different epidemiological settings and populations with samples and data collected in a standardised way. The ideal approach for this will be the GC-6-74 TB consortium repository samples which consists of five African countries including Ethiopia, Uganda, South Africa, The Gambia and Malawi. We suggest further biomarker research by including extrapulumonary TB patients and children where the need of better TB diagnostics is enormous; and from other easy to access specimens including urine, saliva and sputum. To increase the efficiency of biomarker discovery and consecutively to deliver novel clinical tests, there is a need of better understanding of the TB biomarker research process (from study design to validation). Nonetheless, research aimed to understand host-pathogen interactions, the interplay between innate and adaptive immune responses, and the complex cytokine interplay need to be continued.