P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis

Frontiers in Cellular and Infection Microbiology

Helder Imoto Nakaya¹  Mario Hiroyuki Hirata¹  Juan Carlo Santos e Silva¹  Bruno Marcel Silva de Melo²  José Carlos Farias Alves-Filho²  José Maria Alvarez³  Gislane de Almeida-Santos³  Caio César Barbosa Bomfim³  Marcos Vinícios Pinheiro Cione³  Igor Santiago-Carvalho³  Paula Carolina de Souza³  Maria Regina D’Império Lima³  Eduardo Pinheiro Amaral⁴  Elena Lasunskaia⁵ 

[1] Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas (FCF), USP, São Paulo, Brazil;Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, USP, São Paulo, Brazil;Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, Brazil;Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States;Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Brazil;

关键词: tuberculosis;    lung damage;    adjuvant treatment;    P2X7 receptor;    host-direct therapies;   

DOI  :  10.3389/fcimb.2021.672472

来源: Frontiers

【 摘 要 】

The risk of developing severe forms of tuberculosis has increased by the acquired immunodeficiency syndrome (AIDS) epidemic, lack of effective drugs to eliminate latent infection and the emergence of drug-resistant mycobacterial strains. Excessive inflammatory response and tissue damage associated with severe tuberculosis contribute to poor outcome of the disease. Our previous studies using mice deficient in the ATP-gated ionotropic P2X7 receptor suggested this molecule as a promising target for host-directed therapy in severe pulmonary tuberculosis. In this study, we assessed the effects of P2X7 pharmacological blockade on disease severity. First, we observed an increase in P2RX7 gene expression in the peripheral blood of tuberculosis patients compared to healthy donors. Lung leukocytes of mice infected with hypervirulent mycobacteria also showed increased expression of the P2X7 receptor. P2X7 blockade in mice with advanced tuberculosis recapitulated in many aspects the disease in P2X7-deficient mice. P2X7-directed therapy reduced body weight loss and the development of inflammatory and necrotic lung lesions, as well as delayed mycobacterial growth. Lower TNF-α production by lung cells and a substantial reduction in the lung GR-1+ myeloid cell population were observed after P2X7 inhibition. The effector CD4+ T cell population also decreased, but IFN-γ production by lung cells increased. The presence of a large population with characteristics of myeloid dendritic cells, as well as the increase in IL-6 production by lung cells, also indicate a qualitative improvement in the pulmonary immune response due to P2X7 inhibition. These findings support the use of drugs that target the P2X7 receptor as a therapeutic strategy to improve the outcome of pulmonary tuberculosis.

【 授权许可】

CC BY