Distinct Toll-like Receptor Signals Regulate Cerebral Parasite Load and Interferon &agr;/&bgr; and Tumor Necrosis Factor &agr;-Dependent T-Cell Infiltration in the Brains of Trypanosoma brucei-Infected Mice.

Background. The penetration of T cells and trypanosomes into the brain parenchyma is a major pathogenetic event in African trypanosomiasis. Methods. The role of innate immune responses in the penetration of T cells and Trypanosoma brucei brucei into the brain was studied in knockout mice by using double immunofluorescent staining and real-time polymerase chain reaction. Results. We demonstrate that Toll-like receptor (TLR)-MyD88-mediated signaling is required for T-cell and parasite penetration into the brain and microglial activation, besides controlling parasitemia and antigen-specific T-cell activation. Among different TLR-deficient mice studied, TLR9 mediated parasitemia control and T-cell penetration into the brain. TLR-MyD88 signals increased levels of interferon (IFN) &bgr; and tumor necrosis factor (TNF) &agr; transcripts in the brains of infected mice and both TNF-&agr; and IFN-&agr;/&bgr;, receptors promoted T-cell and trypanosoma infiltration into the brain parenchyma. Both resident and infiltrating inflammatory cells in the brain controlled parasite densities in a TLR2- and TLR9-MyD88-mediated manner. However, neither IFN-&agr;/&bgr; nor TNF-&agr; contributed to parasite control in the brain. Conclusions. Our data indicate that innate immune TLR signals stimulate the expression of TNF-&agr; and IFN-&agr/&bgr; that initiate brain invasion of T cells and trypanosomes, and control T. brucei brucei load in the brain by molecules distinct from these. [ABSTRACT FROM AUTHOR]

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