Role of myeloid derived suppressor cells and its purinergic regulation in severe tuberculosis

Abstract

Tuberculosis (TB) is a disease caused by acid-alcohol resistant bacilli, which have high prevalence rate in the world. About one-third of the world population is infected with Mycobacterium tuberculosis (Mtb) and 10% of them will develop the disease. The mycobacteria have acquired genetic mutations that increase their virulence and resistance to chemotherapeutic drugs. Recent research from our laboratory suggests that mice infected with hypervirulent MP287/03 strain of Mycobacterium bovis, which induce severe TB, present in the lungs a cell population with the characteristics of MDSCs (myeloid-derived suppressor cells). This population is composed of immature myeloid cells that have an immunosuppressive potential. Some studies revealed that the immunosuppressive activity of MDSCs is partially mediated by CD39 and CD73 ectonucleotidases that metabolize ATP and ADP to AMP, and AMP to adenosine, respectively. The increase of extracellular adenosine concentrations induces activation of adenosine receptor, which promotes several cellular responses that aim to restore tissue homeostasis. Suppression of effector T cells and induction of M2 macrophage polarization are some effects of adenosine receptor signaling. In this project, we intend: 1) to characterize the population of MDSC-like cells that are present in the lungs of mice suffering from severe TB; 2) to assess if MDSCs induce aggravation of TB; 3) to investigate the effect of A2b adenosine receptor antagonist, as well as CD39 and CD73 ectonucleotidase inhibitors in disease development; and 4) to evaluate whether adenosine generation via CD39 and CD73 ectonucleotidases expressed in MDSCs contributes to immunosuppression and, consequently, to bacterial growth and aggravation of the disease. This study is very relevant because the understanding of the mechanisms involved in the pathogenesis of severe TB opens the perspectives for the development of new therapeutic approaches aiming to attenuate the disease progression. (AU)