P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages.
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.
Lees
Michael P
MP
Institute for the Biotechnology of Infectious Diseases, University of Technology, Sydney, Broadway, NSW, Australia.
Fuller
Stephen J
SJ
McLeod
Rima
R
Boulter
Nicola R
NR
Miller
Catherine M
CM
Zakrzewski
Alana M
AM
Mui
Ernest J
EJ
Witola
William H
WH
Coyne
Jessica J
JJ
Hargrave
Aubrey C
AC
Jamieson
Sarra E
SE
Blackwell
Jenefer M
JM
Wiley
James S
JS
Smith
Nicholas C
NC
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000378:metabolism
C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D009569:Nitric Oxide