Evaluation of the role of the P2X7 receptor in the generation of different subtypes of CD4+ t lymphocytes in severe pulmonary tuberculosis

Abstract

Tuberculosis remains an important public health problem aggravated by the appearance of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains (MDR-TB). Delayed initiation of treatment, high virulence of the infecting strain and susceptibility of the individual to tuberculosis contribute to the severity of the disease, which is often associated with a deleterious inflammatory response, leading to pulmonary necrosis. Infection of the pulmonary macrophages by bacilli and the uncontrolled proliferation of these within the cells cause necrotic death. The released bacilli can infect new cells and thus initiate a new replication cycle. In addition to the dissemination of Mtb, the release of DAMPs (Damage-associated molecular patterns) occurs. The ATP released by dying cells is a danger signal that leads to a proinflammatory response, whereas adenosine, the degradation product of ATP by CD39 and CD73 ecto-nucleotidases, is immunosuppressive. Extracellular ATP may be recognized by purinergic receptors expressed on immune cells. Little is known about the participation of signaling through purinergic receptors on the immune response and on the pathogenesis of tuberculosis. Recently, we have shown that P2X7 purinergic receptor signaling by ATP contributes to the development of severe forms of the disease resulting from infection with hypervirulent strains. However, it is still unclear whether the P2X7 receptor affects the CD4 + T lymphocyte response during tuberculosis. In the present project we have as objectives: 1) To evaluate the participation of the P2X7 receptor in the generation and activation of protective CD4+ T lymphocytes; 2) To evaluate the participation of the P2X7 receptor in the generation of intravascular and parenchymal CD4+ T lymphocytes. We understand that the study of these receptors can contribute to the understanding of the immune response against tuberculosis, as well as open the way to new therapeutic approaches using inhibitors of these receptors as an aid in the treatment of tuberculosis.