The induction of acute ileitis by a single microbial antigen of Toxoplasma gondii.
The role of specific microbial Ags in the induction of experimental inflammatory bowel disease is poorly understood. Oral infection of susceptible C57BL/6 mice with Toxoplasma gondii results in a lethal ileitis within 7-9 days postinfection. An immunodominant Ag of T. gondii (surface Ag 1 (SAG1)) that induces a robust B and T cell-specific response has been identified and a SAG1-deficient parasite (Deltasag1) engineered. We investigated the ability of Deltasag1 parasite to induce a lethal intestinal inflammatory response in susceptible mice. C57BL/6 mice orally infected with Deltasag1 parasites failed to develop ileitis. In vitro, the mutant parasites replicate in both enterocytes and dendritic cells. In vivo, infection with the mutant parasites was associated with a decrease in the chemokine and cytokine production within several compartments of the gut-associated cell population. RAG-deficient (RAG1(-/-)) mice are resistant to the development of the ileitis after T. gondii infection. Adoptive transfer of Ag-specific CD4(+) effector T lymphocytes isolated from C57BL/6-infected mice into RAG(-/-) mice conferred susceptibility to the development of the intestinal disease. In contrast, CD4(+) effector T lymphocytes from mice infected with the mutant Deltasag1 strain failed to transfer the pathology. In addition, resistant mice (BALB/c) that fail to develop ileitis following oral infection with T. gondii were rendered susceptible following intranasal presensitization with the SAG1 protein. This process was associated with a shift toward a Th1 response. These findings demonstrate that a single Ag (SAG1) of T. gondii can elicit a lethal inflammatory process in this experimental model of pathogen-driven ileitis.
Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
Nicolas
N
Rachinel
Dominique
D
Buzoni-Gatel
Chaitali
C
Dutta
Franck J D
FJ
Mennechet
Souphalone
S
Luangsay
Laurie A
LA
Minns
Michael E
ME
Grigg
Stanislas
S
Tomavo
John C
JC
Boothroyd
Lloyd H
LH
Kasper
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007079:Ileitis / Q000276:immunology / Q000469:parasitology*; D007422:Intestines / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D009154:Mutation; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014122:Toxoplasma / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000473:pathology*
D000953:Antigens, Protozoan; D016207:Cytokines; D018398:Homeodomain Proteins; D015800:Protozoan Proteins; C047168:SAG1 antigen, Toxoplasma; C064658:RAG-1 protein