Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM

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 hun...

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Bibliographic Details
Published in:Journal of Immunology 2007-01, Vol.178 (2), p.1068-1076
Main Authors: Hise, Amy G, Daehnel, Katrin, Gillette-Ferguson, Illona, Cho, Eun, McGarry, Helen F, Taylor, Mark J, Golenbock, Douglas T, Fitzgerald, Katherine A, Kazura, James W, Pearlman, Eric
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - immunology
Animals
Brugia malayi
Brugia malayi - immunology
Cell Line
Humans
Immunity, Innate - immunology
Inflammation - immunology
Inflammation - microbiology
Interleukin-6 - biosynthesis
Macrophages - immunology
Macrophages - metabolism
Membrane Transport Proteins - immunology
Mice
Mice, Inbred C57BL
Myelin and Lymphocyte-Associated Proteolipid Proteins
Myelin Proteins - immunology
Myeloid Differentiation Factor 88 - immunology
Nematoda
Onchocerca volvulus
Onchocerca volvulus - immunology
Proteolipids - immunology
Receptors, Interleukin - immunology
Rickettsiaceae Infections - immunology
Rickettsiaceae Infections - microbiology
Symbiosis - immunology
Toll-Like Receptor 2 - immunology
Toll-Like Receptor 4 - immunology
Toll-Like Receptor 6 - immunology
Toll-Like Receptors - immunology
Tumor Necrosis Factor-alpha - biosynthesis
Wolbachia
Wolbachia - immunology
Wolbachia - isolation & purification
Wuchereria - immunology
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Summary: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-beta and Toll/IL-1R domain-containing adaptor-inducing IFN-beta-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.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.178.2.1068