title: 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.
abstract: 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.
authors.affiliation: Center for Global Health and Diseases and Department of Ophthalmology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. amy.hise@case.edu
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.forename: Katrin
authors.initials: K
authors.lastname: Daehnel
authors.forename: Illona
authors.initials: I
authors.lastname: Gillette-Ferguson
authors.forename: Eun
authors.initials: E
authors.lastname: Cho
authors.forename: Helen F
authors.initials: HF
authors.lastname: McGarry
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Taylor
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: James W
authors.initials: JW
authors.lastname: Kazura
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D017178:Brugia malayi / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000276:immunology*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D017181:Onchocerca volvulus / Q000276:immunology*; D011510:Proteolipids / Q000276:immunology*; D018123:Receptors, Interleukin / Q000276:immunology; D012288:Rickettsiaceae Infections / Q000276:immunology / Q000382:microbiology; D013559:Symbiosis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020577:Wolbachia / Q000276:immunology* / Q000302:isolation & purification; D014957:Wuchereria / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015850:Interleukin-6; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; D018123:Receptors, Interleukin; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C569026:MAL protein, human; C569027:Mal protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse; C495369:Tlr6 protein, mouse