Dysregulation of the inflammatory response to the parasite, Toxoplasma gondii, in P2X7 receptor-deficient mice.
The P2X(7) receptor (P2X(7)R) is a two transmembrane receptor that is highly expressed on the surface of immune cells. Loss of function polymorphisms in this receptor have been linked to increased susceptibility to intracellular pathogens. P2X(7)R gene knockout (P2X(7)R(-/-); on a C57Bl/6J background), C57Bl/6J and BALB/c mice were infected with the avirulent ME49 strain of the intracellular parasite, Toxoplasma gondii, and susceptibility determined by monitoring weight loss. P2X(7)R(-/-) mice lost significantly more weight than C57Bl/6J mice from day 8p.i. C57Bl/6J, in turn, lost significantly more weight than BALB/c mice. Thus, by day 10p.i., P2X(7)R(-/-) mice had lost 5.7 ± 0.7% of their weight versus 2.4 ± 0.6% for C57Bl/6J mice, whereas BALB/c mice had gained 1.9 ± 0.5%; by day 12p.i., P2X(7)R(-/-) mice had lost 15.1±0.6%, C57Bl/6J had lost 10.1±0.8% and BALB/c had lost 4.8 ± 0.8% of their weight. Neither parasite burden nor liver pathology was greater in the P2X(7)R(-/-) mice than in C57Bl/6J mice but BALB/c mice had significantly smaller numbers of parasites and less pathology in their livers than these strains. Absence of the P2X(7) receptor did not affect IFN-γ, IL-12, IL-1β, monocyte chemoattractant protein-1 (MCP-1) or TNF production. However, both P2X(7)R(-/-) and C57Bl/6J mice produced more IL-1β and TNF than BALB/c mice. There was one important point of differentiation between the P2X(7)R(-/-) and C57Bl/6J mice, namely the significantly enhanced and prolonged production of nitric oxide, accompanied by delayed production of IL-10 in the P2X(7)R-deficient mice.
Institute for Biotechnology of Infectious Diseases, University of Technology, Sydney, Broadway, NSW 2007, Australia.
Catherine M
CM
Miller
Alana M
AM
Zakrzewski
Rowan J
RJ
Ikin
Nicola R
NR
Boulter
Marilyn
M
Katrib
Michael P
MP
Lees
Stephen J
SJ
Fuller
James S
JS
Wiley
Nicholas C
NC
Smith
D000818:Animals; D004198:Disease Susceptibility; D007249:Inflammation / Q000276:immunology* / Q000469:parasitology* / Q000503:physiopathology; D016753:Interleukin-10 / Q000096:biosynthesis; D008099:Liver / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency* / Q000235:genetics; D013045:Species Specificity; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology*; D015431:Weight Loss
D058486:Receptors, Purinergic P2X7; D016753:Interleukin-10; D009569:Nitric Oxide