<i>Wolbachia</i> Endosymbiotic Bacteria of <i>Brugia malayi</i> Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner

Turner, Joseph D.; Langley, RJ; Johnston, Kelly L.; Egerton, Gill; Wanji, Samuel; Taylor, Mark J.

doi:10.4049/jimmunol.177.2.1240

Cited by 80 publications

(74 citation statements)

References 43 publications

(47 reference statements)

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“…Oral MIN administration in infected SCID mice for 28 days reduced Wolbachia loads within female Bm below the 90% threshold deemed to irreversibly sterilise filarial tissues in clinical studies, leading to macrofilaricidal effects [33,42,43]. The >90% levels of depletion observed in female macrofilariae derived from drugged SCID Bm infections were consistent with in vivo effects reported following protracted tetracycline treatments in patent Bm infections of gerbils [44] and were reflected in a complete blockade in mf release in drugged animals. Having validated the SCID model system as suitably responsive to a range of filaricidal reference compounds, we tested survival rates of male Onchocerca macrofilariae in either SCID BALB/c or WT BALB/c mice.…”

Section: Discussionsupporting

confidence: 70%

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

Halliday

Guimarães

Tyrer

et al. 2014

Parasites & Vectors

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Background: New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model. Methods: The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brugia malayi (Bm)-parasitized BALB/c SCID mice vs vehicle control (VC). Responses were compared to BALB/c wild type (WT). Onchocerca ochengi male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or Meriones gerbils. Survival was evaluated at 7-15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male Onchocerca. Results: WT and SCID responded with >95% efficacy following ABZ or DEC treatments against Bm larvae (P < 0.0001). IVM was partially filaricidal against Bm larvae in WT and SCID (WT; 39.8%, P = 0.0356 and SCID; 56.7%, P = 0.026). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, P = 0.0194. SCID; 76%, P = 0.0473). FBZ induced a total macrofilaricidal response against adult Bm in WT and SCID (WT; P = 0.0067, SCID; P = 0.0071). MIN induced a >90% reduction in Bm Wolbachia burdens (P < 0.0001) and a blockade of microfilarial release (P = 0.0215) in SCID. Male Onchocerca survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% vs 22% vs 39% P = 0.0475). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae ex vivo. FBZ induced a macrofilaricidal effect in Onchocerca male implanted SCID at +5 weeks (FBZ; 1.67% vs VC; 43.81%, P = 0.0089). Wolbachia loads within male Onchocerca were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.

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Section: Discussionsupporting

confidence: 70%

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

Halliday

Guimarães

Tyrer

et al. 2014

Parasites & Vectors

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“…The role of potential anti-inflammatory factors released by the filaria and the role of adaptive host responses are not addressed in this study and potentially add to the complexity of the pathogenesis of filarial diseases. Turner et al (68) have recently shown that immune tolerance induced by Wolbachia containing Brugia extracts to a range of TLR ligands is dependent on TLR2 and MyD88 but not TLR4. In our recent study of O. volvulus induced neutrophil recruitment in the cornea, Wolbachia-induced production of proinflammatory and chemotactic cytokines, development of corneal haze, and neutrophil activation were completely abrogated in MyD88 Ϫ/Ϫ mice (27), consistent with the data presented in this study.…”

Section: Discussionmentioning

confidence: 99%

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

Hise

Daehnel

Gillette‐Ferguson

et al. 2007

The Journal of Immunology

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106

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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-β and Toll/IL-1R domain-containing adaptor-inducing IFN-β-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.

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“…Another possible explanation for the protective effects that prepatent female adult worms had on LPS challenge is the release of helminth products that directly impede the immune response triggered by LPS, as earlier studies have demonstrated that helminths can secrete products that reduce the responses of Toll-like receptors (TLRs) to LPS. Soluble extracts from Brugia malayi and Schistosoma mansoni reduced the TLR4 expression on macrophages and the ability of TLRs from dendritic cells to respond to LPS (21,31,38). Further studies with female adult L. sigmodontis worms will investigate these possible protective mechanisms with respect to LPS-induced sepsis.…”

Section: Resultsmentioning

confidence: 99%

Microfilariae of the Filarial NematodeLitomosoides sigmodontisExacerbate the Course of Lipopolysaccharide-Induced Sepsis in Mice

et al. 2008

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Helminths facilitate their own survival by actively modulating the immune systems of their hosts. We investigated the impacts that different life cycle stages of the rodent filaria Litomosoides sigmodontis have on the inflammatory responses of mice injected with sublethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from prepatent infections, worms which have not yet started to release microfilariae, developed lower levels of proinflammatory cytokines in the peripheral blood after LPS challenge than shamtreated controls, demonstrating that female adult worms can mitigate the innate immune response. The presence of microfilariae in mice, however, through either direct injection or implantation of microfilariareleasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), interleukin 12 (IL-12), and IL-6, greater numbers of macrophages and granulocytes in the peripheral blood, and decreased body temperatures in microfilaria-infected mice. Microfilaria-infected mice deficient in IFN-␥ receptor and TNF receptor 1 had increased survival rates after LPS challenge compared to immune-competent mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFN-␥ and TNF-␣. In summary, we have demonstrated that infection of mice with L. sigmodontis female adult worms from prepatent infections protects mice injected with LPS whereas microfilariae worsen LPS-induced sepsis through the induction of proinflammatory cytokines and upregulation of granulocytes, NK cells, and monocytes in the peripheral blood.Infections with helminths often cause chronic disease with a wide spectrum of clinical manifestations, ranging from asymptomatic to severe pathology. By actively suppressing the inflammatory responses of their hosts, helminths facilitate their own survival (26). This suppression will not only permit parasite persistence at high infection levels but also avoid pathological changes to the host. Amazingly, the presence of only one female adult worm of the rodent filarial nematode Litomosoides sigmodontis, an animal model for human filariasis (1, 18), is sufficient to prolong the viability of their progeny, the microfilariae, in the host (19). Although microfilariae given alone provoke a Th1 response in their hosts (25), adult filarial worms typically induce a Th2 immune response characterized by high levels of interleukin 4 (IL-4), IL-5, IL-10, IL-13, and immunoglobulin E as well as an augmentation of mast cells, eosinophils, and basophils (26).In addition, helminths induce a stage of hyporesponsiveness in their hosts (14), likely due to a targeted immune suppression by IL-10, transforming growth factor ␤, regulatory T cells, and alternatively activated macrophages (12,16,23,33,36,37). Recently, this immunomodulatory capacity of parasitic worms or their excretory/secretory products has been effectively utilized for therapeutic purposes in patients with inf...

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Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner

Cited by 80 publications

References 43 publications

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

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

Microfilariae of the Filarial NematodeLitomosoides sigmodontisExacerbate the Course of Lipopolysaccharide-Induced Sepsis in Mice

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