The P2x7 Purinergic Receptor and Mycobacterial Infections in Humans: the Role of Loss-of-function Polymorphisms in the Gene for the P2x7 Purinergic Receptor and Mycobacterial Infections in Humans

Tuberculosis (TB) remains an enormous global health problem. The majority of people infected with Mycobacterium tuberculosis are able to contain their infection, however, in approximately 10% of individuals, active disease eventually develops, usually from reactivation of latent infection. HIV coinfection and other environmental causes of reduced T cell immunity predispose to this progression in a proportion of individuals. There is emerging evidence that genetic variation also influences susceptibility to TB. Activation of the P2X7 receptor kills mycobacteria within macrophages. Several polymorphisms in the P2X7 gene impair this killing. The most common of these polymorphisms was strongly associated with extrapulmonary TB in two separate cohorts in a Sydney population. Furthermore, ATP-mediated killing of mycobacteria was significantly impaired in macrophages from heterozygous subjects and ablated in macrophages from subjects homozygous for this polymorphism. By contrast, no loss-of-function polymorphism was associated with clinical leprosy in a Nepali population. P2X7-mediated killing of mycobacteria can be augmented with stimulation of certain cytokines.