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International Immunology Advance Access originally published online on November 29, 2006
International Immunology 2007 19(1):67-79; doi:10.1093/intimm/dxl123
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Pathological role of Toll-like receptor signaling in cerebral malaria

Cevayir Coban1,2,*, Ken J. Ishii1,3,*, Satoshi Uematsu1, Nobuko Arisue4, Shintaro Sato1,3, Masahiro Yamamoto1, Taro Kawai1,3, Osamu Takeuchi1,3, Hajime Hisaeda5, Toshihiro Horii4 and Shizuo Akira1,2,3

1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
2 21st Century Center of Excellence, Combined Program on Microbiology and Immunology, Osaka University, Suita, Osaka 565-0871, Japan
3 Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, Suita, Osaka 565-0871, Japan
4 Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
5 Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

Correspondence to: S. Akira; E-mail: sakira{at}biken.osaka-u.ac.jp

Toll-like receptors (TLRs) recognize malaria parasites or their metabolites; however, their physiological roles in malaria infection in vivo are not fully understood. Here, we show that myeloid differentiation primary response gene 88 (MyD88)-dependent TLR signaling mediates brain pathogenesis of severe malaria infection, namely cerebral malaria (CM). A significant number of MyD88-, but not TIR domain containing adaptor-inducing IFN-beta (TRIF)-deficient or wild-type (WT) mice survived CM caused by Plasmodium berghei ANKA (PbA) infection. Although systemic parasitemia was comparable, sequestration of parasite and hemozoin load in the brain blood vessels was significantly lower in MyD88-deficient mice compared with those in TRIF-deficient or WT mice. Moreover, brain-specific pathological changes were associated with MyD88-dependent infiltration of CD8+, CCR5+ T cells and CD11c+ dendritic cells, including CD11c+, NK1.1+ and B220+ cells, and up-regulation of genes such as Granzyme B, Lipocalin 2, Ccl3 and Ccr5. Further studies using mice lacking various TLRs suggest that TLR2 and TLR9, but not TLR4, 5 and 7, were involved in CM. These results strongly suggest that TLR2- and/or TLR9-mediated, MyD88-dependent brain pathogenesis may play a critical role in CM, the lethal complication during PbA infection.

Keywords: cell trafficking, hemozoin, innate immunity, MyD88, Plasmodium

* These authors contributed equally to this study.

Transmitting editor: K. Inaba


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