A loss-of-function polymorphism in the human P2X7 receptor abolishes ATP-mediated killing of mycobacteria.
Protective immunity to mycobacterial infections requires activation of the antibacterial mechanisms of infected macrophages. It has previously been reported that ATP treatment of mycobacteria-infected macrophages induces apoptosis mediated via the P2X(7) pathway and that this leads to the death of both the host cell and the internalized bacilli. We have recently identified a single nucleotide polymorphism in the P2X7 gene (1513A-->C), with 1-2% prevalence in the homozygous state, which codes for a nonfunctional receptor. IFN-gamma-primed, mycobacteria-infected macrophages from wild-type individuals were incubated with ATP and this induced apoptosis and reduced mycobacterial viability by 90%. Similar treatment of macrophages from individuals homozygous for the 1513C polymorphism failed to induce apoptosis and did not lead to mycobacterial killing via the P2X(7)-mediated pathway. These data demonstrate that a single nucleotide polymorphism in the P2X7 gene can allow survival of mycobacteria within infected host cells.
Saunders
Bernadette M
BM
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW Australia. b.saunders@centenary.usyd.edu.au
Fernando
Suran L
SL
Sluyter
Ronald
R
Britton
Warwick J
WJ
Wiley
James S
JS
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology*; D000328:Adult; D000483:Alleles; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D006720:Homozygote; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology / Q000502:physiology*; D009163:Mycobacterium bovis / Q000254:growth & development* / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7
C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate