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

• Grant number: 14/22986-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2015
• End date: July 03, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Caio César Barbosa Bomfim
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 17/09110-4 - Morphological and Functional Characterization of Immature Myeloid Cells in Severe Tuberculosis, BE.EP.DR

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARBOSA BOMFIM, CAIO CESAR; AMARAL, EDUARDO PINHEIRO; CASSADO, ALEXANDRA DOS ANJOS; SALLES, ERIKA MACHADO; DO NASCIMENTO, ROGERIO SILVA; LASUNSKAIA, ELENA; HIRATA, MARIO HIROYUKI; ALVAREZ, JOSE MARIA; D'IMPERIO-LIMA, MARIA REGINA. P2X7 receptor in Bone Marrow-Derived cells aggravates Tuberculosis caused by hypervirulent Mycobacterium bovis. FRONTIERS IN IMMUNOLOGY, v. 8, APR 13 2017. (12/22587-0, 14/22986-8, 15/20432-8, 13/07140-2)

BARBOSA BOMFIM, CAIO CESAR; AMARAL, EDUARDO PINHEIRO; SANTIAGO-CARVALHO, IGOR; SANTOS, GISLANE ALMEIDA; SALLES, ERIKA MACHADO; HASTREITER, ARACELI APARECIDA; DO NASCIMENTO, ROGERIO SILVA; ALMEIDA, FABRICIO M.; BIA VENTURA SIMAO, THATIANA LOPES; REZENDE, ANDREZA LINHARES; et al. Harmful Effects of Granulocytic Myeloid-Derived Suppressor Cells on Tuberculosis Caused by Hypervirulent Mycobacteria. Journal of Infectious Diseases, v. 223, n. 3, p. 494-507, FEB 1 2021. (15/20432-8, 17/09110-4, 14/22986-8)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BOMFIM, Caio César Barbosa. Tuberculosis (TB) is an infectious disease caused by bacteria belonging to M.tuberculosis complex.. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.