CD39 regulates P2RX7-mediated lung necrotic lesions in severe experimental tuberculosis

Abstract

Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in the development of severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in tuberculosis progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cell surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We propose that, by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis.