PNNL

Abstract

Rationale: Contemporary phase 2 TB clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for developing new TB drugs and regimens. Objective: We sought to serially characterize clinical features and proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host biomarkers in clinical trial participants enrolled in African and Non-African regions. Methods: Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29?(NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). Serum proteins were immunoaffinity-depleted of high abundant components, digested to peptides and analyzed for data acquisition utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS). Measurements and Main Results: A total of 183 proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathway. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways. Conclusions: The identification of differentially expressed proteins by African versus non-African regions, particularly in relation to nutrition and lipid pathways, suggests that microbiologic treatment responses may be impacted by nutritional status, and interventions for enhancing nutrition may have positive effects on outcomes.