International Immunology Advance Access published online on October 11, 2006
International Immunology, doi:10.1093/intimm/dxl099
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1 Division of Infectious Genetics, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108-8639, Japan
* To whom correspondence should be addressed. Peroral infection of Toxoplasma gondii is thought to reflect the typical infection route of naturally acquired toxoplasmosis in humans. We have investigated possible differential roles of toll-like receptor 2 (TLR2) and TLR4 in host defense against naturally acquired murine toxoplasmosis. After peroral inoculation of T. gondii ME49 cysts, TLR4-deficient C3H/HeJ mice were more susceptible to infection than wild-type (WT) C3H/HeN mice, as shown by increased cyst number and low production of cytokines, which are the key factors in protective immunity. When mice were inoculated by intra-peritoneal inoculation of T. gondii, there were no significant differences in the number of brain cysts and cytokine productions between C3H/HeJ and C3H/HeN mice. Histopathologic examination revealed severe inflammation in the small intestine of C3H/HeJ (TLR4-deficient) mice, while an increased number of TLR4-positive mononuclear cells was found in C3H/HeN (WT) mice. To confirm these phenomena, TLR2-/- or TLR4-/- mice were infected perorally with T. gondii cysts. TLR4-/- mice were more susceptible to infection compared with TLR2-/- and C57BL/6 mice. Nuclear factor-kappa B activation through TLR4 agonistic activity of T. gondii ME49 was demonstrated by luciferase assay using stably expressing mouse (m) TLR2 or mTLR4/mMD-2 transfectants. We demonstrate here for the first time that innate immune recognition by TLR4 is involved in protective mechanisms against peroral infection with T. gondii ME49. These results suggest that the small intestine plays an important role in the induction of innate immunity in naturally acquired toxoplasmosis.
Received April 10, 2006
Accepted September 8, 2006
Article
Roles of the small intestine for induction of toll-like receptor 4-mediated innate resistance in naturally acquired murine toxoplasmosis
Takahisa Furuta 1 *, Takane Kikuchi 2, Shizuo Akira 3, Naohiro Watanabe 4, and Yasuhiro Yoshikawa 5
2 Division of Infectious Genetics, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108-8639, Japan; Present address: Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, 1925 Coffey Road, Columbus, OH 43210-1093, USA
3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 665-0871, Japan
4 Department of Tropical Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan
5 Department of Biomedical Science, Graduate School of Agricultural and Life Science, University of Tokyo, Tokyo 113-8657, Japan
Takahisa Furuta, E-mail: furuta{at}ims.u-tokyo.ac.jp
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