Dysregulation of the inflammatory response to the parasite, Toxoplasma gondii, in P2X7 receptor-deficient mice

• Published in: International journal for parasitology Vol. 41; no. 3-4; pp. 301 - 308
• Main Authors: Miller, Catherine M., Zakrzewski, Alana M., Ikin, Rowan J., Boulter, Nicola R., Katrib, Marilyn, Lees, Michael P., Fuller, Stephen J., Wiley, James S., Smith, Nicholas C.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.03.2011; [Oxford; New York]: Elsevier Science; Elsevier
• Subjects: Animals; Apicomplexa; Biological and medical sciences; Disease Susceptibility; Fundamental and applied biological sciences. Psychology; IL-10; Immunopathology; Inflammation - immunology; Inflammation - parasitology; Inflammation - physiopathology; Interleukin-10 - biosynthesis; Life cycle. Host-agent relationship. Pathogenesis; Liver - parasitology; Liver - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nitric oxide; Nitric Oxide - biosynthesis; P2X7 receptor; Protozoa; Receptors, Purinergic P2X7 - deficiency; Receptors, Purinergic P2X7 - genetics; Species Specificity; Toxoplasma - immunology; Toxoplasma - pathogenicity; Toxoplasma gondii; Toxoplasmosis, Animal - genetics; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - parasitology; Toxoplasmosis, Animal - physiopathology; Weight Loss; Immunopathology; Apicomplexa; Toxoplasma gondii; P2X7 receptor; Nitric oxide; IL-10; Protozoa; Rodentia; Parasite; Vertebrata; Mammalia; receptor; Mouse; P2X
• ISSN: 0020-7519; 1879-0135
• DOI: 10.1016/j.ijpara.2010.10.001

[Display omitted] ► Mice lacking P2X7 receptor function (P2X7R knockout) lost more weight than C57Bl/6J mice (partial P2X7R function) and BALB/c mice (full P2X7R function) after infection with Toxoplasma. ► Absence of the P2X7R did not affect IFN-γ, IL-12, IL-1β or TNF production. ► P2X7R knockout mice had prolonged production of nitric oxide after infection with Toxoplasma. ► P2X7R knockout mice had delayed production of IL-10 after infection with Toxoplasma. The P2X7 receptor (P2X7R) 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. P2X7R gene knockout (P2X7R−/−; 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. P2X7R−/− 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., P2X7R−/− 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., P2X7R−/− 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 P2X7R−/− 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 P2X7 receptor did not affect IFN-γ, IL-12, IL-1β, monocyte chemoattractant protein-1 (MCP-1) or TNF production. However, both P2X7R−/− and C57Bl/6J mice produced more IL-1β and TNF than BALB/c mice. There was one important point of differentiation between the P2X7R−/− and C57Bl/6J mice, namely the significantly enhanced and prolonged production of nitric oxide, accompanied by delayed production of IL-10 in the P2X7R-deficient mice.