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* Center for Global Health and Diseases and
Department of Ophthalmology, Case Western Reserve University, Cleveland, OH 44106;
Division of Infectious Disease & Immunology, University of Massachusetts Medical School, Worcester, MA 01655; and
Filariasis Research Laboratory, Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
The discovery that endosymbiotic Wolbachia bacteria play an important role in the pathophysiology of diseases caused by filarial nematodes, including lymphatic filariasis and onchocerciasis (river blindness) has transformed our approach to these disabling diseases. Because these parasites infect hundreds of millions of individuals worldwide, understanding host factors involved in the pathogenesis of filarial-induced diseases is paramount. However, the role of early innate responses to filarial and Wolbachia ligands in the development of filarial diseases has not been fully elucidated. To determine the role of TLRs, we used cell lines transfected with human TLRs and macrophages from TLR and adaptor molecule-deficient mice and evaluated macrophage recruitment in vivo. Extracts of Brugia malayi and Onchocerca volvulus, which contain Wolbachia, directly stimulated human embryonic kidney cells expressing TLR2, but not TLR3 or TLR4. Wolbachia containing filarial extracts stimulated cytokine production in macrophages from C57BL/6 and TLR4–/– mice, but not from TLR2–/– or TLR6–/– mice. Similarly, macrophages from mice deficient in adaptor molecules Toll/IL-1R domain-containing adaptor-inducing IFN-
and Toll/IL-1R domain-containing adaptor-inducing IFN--related adaptor molecule produced equivalent cytokines as wild-type cells, whereas responses were absent in macrophages from MyD88–/– and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice. Isolated Wolbachia bacteria demonstrated similar TLR and adaptor molecule requirements. In vivo, macrophage migration to the cornea in response to filarial extracts containing Wolbachia was dependent on TLR2 but not TLR4. These results establish that the innate inflammatory pathways activated by endosymbiotic Wolbachia in B. malayi and O. volvulus filaria are dependent on TLR2-TLR6 interactions and are mediated by adaptor molecules MyD88 and TIRAP/Mal.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants K08 AI054652 (to A.G.H.), AI-07024 (to I.G.-F.), EY10320, and EY11373 from the National Institutes of Health and by the Research to Prevent Blindness Foundation (to E.P.), the Ohio Lions Eye Research Foundation (to E.P.), and the Wellcome Trust for Senior Fellowship (to M.J.T.).
2 Address correspondence and reprint requests to Dr. Amy G. Hise, Center for Global Health and Diseases, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-7286. E-mail address: amy.hise{at}case.edu
3 Abbreviations used in this paper: TIRAP, Toll/IL-1R domain-containing adaptor protein; Mal, MyD88-adaptor-like; WSP, Wolbachia surface protein; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-; TRAM, TRIF-related adaptor molecule.
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