Pathological role of Toll-like receptor signaling in cerebral malaria.
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.
Coban
Cevayir
C
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Ishii
Ken J
KJ
Uematsu
Satoshi
S
Arisue
Nobuko
N
Sato
Shintaro
S
Yamamoto
Masahiro
M
Kawai
Taro
T
Takeuchi
Osamu
O
Hisaeda
Hajime
H
Horii
Toshihiro
T
Akira
Shizuo
S
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D001921:Brain / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D006420:Hemeproteins / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010962:Plasmodium berghei; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D006420:Hemeproteins; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; C020753:hemozoin