P2X7 Receptor-Mediated Killing of an Intracellular Parasite,Toxoplasma gondii, by Human and Murine Macrophages

Abstract

The P2X7R is highly expressed on the macrophage cell surface, and activation of infected cells by extracellular ATP has been shown to kill intracellular bacteria and parasites. Furthermore, single nucleotide polymorphisms that decrease receptor function reduce the ability of human macrophages to kill Mycobacterium tuberculosis and are associated with extrapulmonary tuberculosis. In this study, we show that macrophages from people with the 1513C (rs3751143, NM_002562.4:c.1487A>C) loss-of-function P2X7R single nucleotide polymorphism are less effective in killing intracellular Toxoplasma gondii after exposure to ATP compared with macrophages from people with the 1513A wild-type allele. Supporting a P2X7R-specific effect on T. gondii, macrophages from P2X7R knockout mice (P2X7R−/−) are unable to kill T. gondii as effectively as macrophages from wild-type mice. We show that P2X7R-mediated T. gondii killing occurs in parallel with host cell apoptosis and is independent of NO production.

Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

“…In infected murine macrophages, P2X 7 R activation can induce cell death to prevent parasite replication (8,10). In addition, in IFN-␥-activated murine embryonic fibroblasts (MEFs), infected host cells undergo necrotic cell death after IRG-mediated disruption of the parasitophorous vacuole (44).…”

“…For instance, in mouse and human macrophages, CD40 stimulation induces autophagic killing of the parasite by fusion of parasitophorous vacuoles with lysosomes (7). In addition, activation of the purinergic receptor P2X7R leads to killing of the parasite in murine and human macrophages, and killing is associated with fusion of the parasitophorous vacuole with lysosomes or apoptotic death in murine macrophages (8,9). The NALP1 inflammasome receptor was also identified as a susceptibility locus for human congenital toxoplasmosis, and silencing NALP1 leads to uncontrolled parasite growth in human monocytes (10).…”

Lack of Association of 1513 A/C Polymorphism in P2X7 Gene with Susceptibility to Pulmonary and Extrapulmonary Tuberculosis

“…The more relevant SNPs of P2X 7 reported correspond to the 1513A/C that affects the carboxy terminal tail and leads to a loss of receptor function as assessed by ATP induced Ca 2+ ethidium bromide influx and IL-1β release (14)(15)(16)(17)(18). Previous studies have shown that macrophages from individuals homozygous for the 1513C loss of function allele have complete loss of receptor function while individual heterozygous for this polymorphism still maintain 50% function to kill intracellular parasites such as M. tuberculosis or T. gondii after exposure to ATP compared with maci rophages from individuals with the 1513A wild type allele (17,18). This study indicates that there is no risk between 1513A/C polymorphism in the P2X 7 gene and tuberculosis disease in the Eastern Turkey.…”

P2X7 receptor in skin biology and diseases

“…Direct evidence for P2X7 on dermal macrophages is lacking, but it is well established that this receptor is present on human and murine macrophages derived from monocytes [46][47][48] or isolated from tissues [49,50] . P2X7 activation on human and murine macrophages results in the release of proinflammatory mediators such as IL-1b and prostaglandin E2 [51] , as well as the production of reactive oxygen species [52] , and killing of intracellular mycobacteria [53] , chlamydia [54] and toxoplasma [55] . Of note, P2X7 activation eliminates Leishmania amazonensis, the causative agent of human cutaneous leishmaniasis [56] , within murine peritoneal macrophages [57] , supporting the potential importance of macrophage P2X7 in skin biology.…”