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

Infection with Mycobacterium tuberculosis can cause diverse lesions, such as necrotic pneumonia, which can contribute to tuberculosis progression and transmission between individuals. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in the development of severe forms of the disease, 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 cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. Cell-intrinsic CD39 expression also hinders the establishment of other myeloid cells, such as neutrophils, in the infected lung. We proposed that, by protecting infected macrophages from P2RX7-mediated cell death and bacterial dissemination in the lung tissue, 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.