Evolving immune response and gut microbiota patterns during tuberculosis management – PRIM-TB

Mycobacterium tuberculosis (Mtb) is responsible of clinical conditions going from latent tuberculosis (TB) infection (LTBI) to active TB. Real-time biomarkers for diagnosis of both active TB and LTBI, and for therapeutic efficacy are mostly needed. Among host immune effectors preventing active TB development, several T-cell subsets have been proposed as biomarker candidates. Besides CD4+ T-cells which are critical for Mtb control, mucosal associated invariant T cells (MAIT cells) dramatically decrease in active TB and restore upon treatment. MAIT cells react against a newly identified class of antigens: metabolites of vitamin B, which are found in most bacteria resident of the gut microbiota (GM). It is assumed that MAIT cells development and function are linked to GM homeostatsis. Moreover, altered GM patterns were observed in TB subjects, resulting in increased production of short chain fatty acid and decreased vitamin B metabolism, correlated with low levels of CD4+T-cells in the peripheral blood and therefore supposed to impair host’s immunity.
The PRIM-TB project proposes a multidisciplinary translational approach to decipher the complex interplay between GM and host’s immunity in the clinical setting of Mtb-infected patients. The first objective is to identify or validate surrogate biomarkers of disease progression and treatment efficacy in active TB-treated patients. For that purpose we will investigate the dynamics of host innate and adaptive immune responses to Mtb among a cohort of LTBI and active TB patients using peripheral blood flow cytometry, transcriptomics and proteomics.
The second objective is to determine whether the composition and the functionality of T-cells are influenced by the GM dynamics during the course of TB treatment. Therefore we will contemporaneously monitor GM composition and function throughout TB treatment.
The scientific coordinator will interact with the scientific partners involved in the TB-PRIM project providing exceptional resources to patient samples, and expertise in immunology, GM analysis and statistical analysis. This project will give the opportunity to the scientific coordinator to reinforce the emergent local collaborative network in the field of TB, known as the Lyon TB study group.
This project will describe the evolution T-cell subsets, in parallel with GM composition and function, throughout TB treatment, with the aim to decipher how both kinetics influence each other as well as the patient’s outcome. Ultimately, this study will determine how and when GM and immune cell interactions are involved in the Mtb infection control, an indispensable step to design predictive biomarkers and ultimately propose new therapeutic options.