The Experts below are selected from a list of 2712 Experts worldwide ranked by ideXlab platform
Eric Pearlman - One of the best experts on this subject based on the ideXlab platform.
-
Filaria wolbachia activation of dendritic cells and development of th1 associated responses is dependent on toll like receptor 2 in a mouse model of ocular onchocerciasis river blindness
2007Co-Authors: Katrin Daehnel, Illona Gilletteferguson, Amy G. Hise, Eugenia Diaconu, M J Harling, Fred P Heinzel, Eric PearlmanAbstract:Toll-like receptors (TLRs) regulate dendritic cell function and activate signals that mediate the nature of the adaptive immune response. The current study examined the role of TLRs in dendritic cell activation and in regulating T cell and antibody responses to antigens from the Filarial parasites Onchocerca volvulus and Brugia malayi, which cause river blindness and lymphatic Filariasis, respectively. Bone-marrow-derived CD11c(+) cells from C57BL/6 and TLR4(-/-) mice produced high levels of IL-6 and RANTES, and showed elevated surface CD40 expression, whereas CD11c(+) cells from myeloid differentiation factor 88(-/-) (MyD88(-/-)), TLR2(-/-) and TLR2/4(-/-) mice were not activated. Similarly, IFN-gamma production by splenocytes from immunized TLR2(-/-) mice was significantly impaired compared with splenocytes from C57BL/6 and TLR4(-/-) mice. In contrast, there was no difference among these strains in Th2-associated responses including IL-5 production by splenocytes from immunized animals, serum IgE and IgG(1), or eosinophil infiltration into the corneal stroma. Neutrophil recruitment to the cornea and CXC chemokine production was inhibited in immunized TLR2(-/-) mice compared with C57BL/6 and TLR4(-/-) mice. Taken together, these findings demonstrate an essential role for TLR2 in Filaria-induced dendritic cell activation, IFN-gamma production and neutrophil migration to the cornea, but does not affect Filaria-induced Th2-associated responses.
-
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
2007Co-Authors: Amy G. Hise, Illona Gilletteferguson, Helen F Mcgarry, Katrin Daehnel, James W Kazura, Mark J. Taylor, Katherine A Fitzgerald, Douglas T Golenbock, Eric PearlmanAbstract: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.
-
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
2007Co-Authors: Amy G. Hise, Illona Gilletteferguson, Helen F Mcgarry, Katrin Daehnel, James W Kazura, Mark J. Taylor, Katherine A Fitzgerald, Douglas T Golenbock, Eun Wie Cho, Eric PearlmanAbstract: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.
-
cytokine regulation of Filaria induced airway and corneal disease
2000Co-Authors: Eric Pearlman, Rajeev K Mehlotra, Musa A Haxhiu, Laurie R HallAbstract:Approximately 200 million individuals are infected with Filarial helminths, the parasitic helminths that cause lymphatic Filariasis and onchocerciasis (river blindness). Filariae are thread-like nematodes that are transmitted by the bite of blood-sucking arthropods (mosquitoes transmit lymphatic Filariae and black flies transmit onchocerciasis). Adult males and females are viviparous, and the early first stage larvae, termed microfiariae, are present in either the blood (lymphatic Filariae) or the skin (onchocerciasis).
-
interleukin 12 suppresses Filaria induced pulmonary eosinophilia deposition of major basic protein and airway hyperresponsiveness
1998Co-Authors: Rajeev K Mehlotra, James W Kazura, Musa A Haxhiu, Laurie R Hall, Alan W Higgins, Ismail A Dreshaj, Eric PearlmanAbstract:Tropical Pulmonary Eosinophilia (TPE) is a severe form of allergic asthma caused by the host inflammatory response to Filarial helminths in the lung microvasculature, and is characterized by pulmonary eosinophilia, increased Filarial-specific IgG and IgE antibodies, and airway hyperresponsiveness. The current study examined the effect of IL-12 on pulmonary eosinophilia, deposition of eosinophil major basic protein and airway hyperresponsiveness in mice inoculated i.v. with Brugia malayi microFilariae. Injection of recombinant murine IL-12 modulated the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated IFN-γ, and decreased IL-4 and IL-5 production. Consistent with this shift in cytokine response, antigen-specific IgG2a was elevated, and IgG1 and total serum IgE were decreased. In addition, eosinophils in BAL fluid from IL-12 treated mice were reduced from 56% to 11%, and there was no detectable MBP on respiratory epithelial cells. Importantly, IL-12 suppressed airway hyperresponsiveness compared with saline-injected control animals. Taken together, these data clearly demonstrate that by modulating Th associated cytokine production, IL-12 down-regulates Filaria-induced lung immunopathology.
Achim Hoerauf - One of the best experts on this subject based on the ideXlab platform.
-
il 4 receptor dependent expansion of lung cd169 macrophages in microFilaria driven inflammation
2019Co-Authors: Frederic Fercoq, Estelle Remion, Stefan J Frohberger, Nathaly Vallarinolhermitte, Achim Hoerauf, John Le Quesne, Frederic Landmann, Marc P Hubner, Leo M Carlin, C. MartinAbstract:Lung disease is regularly reported in human Filarial infections but the molecular pathogenesis of pulmonary Filariasis is poorly understood. We used Litomosoides sigmodontis, a rodent Filaria residing in the pleural cavity responsible for pleural inflammation, to model responses to human Filarial infections and probe the mechanisms. Wild-type and Th2-deficient mice (ΔdblGata1 and Il-4receptor(r)a-/-/IL-5-/-) were infected with L. sigmodontis. Survival and growth of adult Filariae and prevalence and density of microFilariae were evaluated. Cells and cytokines in the pleural cavity and bronchoalveolar space were characterized by imaging, flow cytometry and ELISA. Inflammatory pathways were evaluated by transcriptomic microarrays and lungs were isolated and analyzed for histopathological signatures. 40% of WT mice were amicrofilaremic whereas almost all mutant mice display blood microfilaremia. MicroFilariae induced pleural, bronchoalveolar and lung-tissue inflammation associated with an increase in bronchoalveolar eosinophils and perivascular macrophages, production of mucus, visceral pleura alterations and fibrosis. Inflammation and pathology were decreased in Th2-deficient mice. An IL-4R-dependent increase of CD169 was observed on pleural and bronchoalveolar macrophages in microfilaremic mice. CD169+ tissue-resident macrophages were identified in the lungs with specific localizations. Strikingly, CD169+ macrophages increased significantly in the perivascular area in microfilaremic mice. These data describe lung inflammation and pathology in chronic Filariasis and emphasize the role of Th2 responses according to the presence of microFilariae. It is also the first report implicating CD169+ lung macrophages in response to a Nematode infection.
-
il 4 5 signalling plays an important role during litomosoides sigmodontis infection influencing both immune system regulation and tissue pathology in the thoracic cavity
2017Co-Authors: Manuel Ritter, Achim Hoerauf, Ruth S E Tamadaho, Judith Feid, Wenzel Vogel, Katharina Wiszniewsky, Sven Perner, Laura E LaylandAbstract:Abstract Approximately 100 million people suffer from Filarial diseases including lymphatic Filariasis (elephantiasis), onchocerciasis (river blindness) and loiasis. These diseases are amongst the most devastating of the neglected tropical diseases in terms of social and economic impact. Moreover, many infection-induced immune mechanisms in the host, their relationship to disease-related symptoms and the development of pathology within the site of infection remain unclear. To improve on current drug therapies or vaccines, further studies are necessary to decipher the mechanisms behind Filaria-driven immune responses and pathology development, and thus the rodent model of Litomosoides sigmodontis can be used to unravel host-Filaria interactions. Interestingly, BALB/c mice develop a patent state (release of microFilariae, the transmission life-stage, into the periphery) when exposed to L. sigmodontis. Thus, using this model, we determined levels of host inflammation and pathology development during a L. sigmodontis infection in vivo for the first known time. Our study reveals that after 30 days p.i., inflammation and pathology began to develop in infected wild type BALB/c mice between the lung and diaphragm, close to the site of infection – the thoracic cavity. Interestingly, infected IL-4Rα/IL-5−/− BALB/c mice had accentuated inflammation of the pleural lung and pleural diaphragm, and higher parasite burdens. Corresponding to the pleural inflammation, levels of IP-10, MIP-1α, MIP-1β, MIP-2 and RANTES were significantly elevated in the thoracic cavity fluid of infected IL-4Rα/IL-5−/− mice compared with wild type controls. Moreover, upon L. sigmodontis antigen stimulation, IFN-γ and IL-17A secretions by cells isolated from draining lymph nodes of IL-4Rα/IL-5−/− mice were significantly elevated, whereas secretion of IL-5, IL-13 and IL-10 was reduced. Elevated Filaria-specific IFN-γ secretion was also observed in spleen-derived CD4+ T cell co-cultures from IL-4Rα/IL-5−/− mice. In summary, this study unravels the essential role of IL-4/IL-5 signalling in controlling immunity against Filarial infections and demonstrates the requirement of this pathway for the host to control ensuing pathology and inflammation.
-
Filaria induced il 10 suppresses murine cerebral malaria
2010Co-Authors: Sabine Specht, Daniel Fernandez Ruiz, Bettina Dubben, Susanne Deininger, Achim HoeraufAbstract:Abstract Filarial nematodes achieve long survival in their hosts due to their capacity to modulate immune responses. Therefore, immunomodulation by Filarial nematodes may alter responses to concomitant infections such as malaria. Cerebral malaria (CM), a severe complication of Plasmodium falciparum infections, is triggered as a consequence of the immune response developed against malaria parasites. The question arises whether prior infection with helminth parasites is beneficial against CM. In the present work a murine model for subsequent has been used to assess this hypothesis. C57BL/6 mice were infected with the rodent Filarial parasite Litomosoides sigmodontis and the murine model parasite for CM, Plasmodium berghei ANKA. Previously Filaria-infected C57BL/6 mice showed significantly reduced CM rates. CD8+ T cell recruitment to the brain, a hallmark for CM development, was reduced in protected mice. Furthermore, in contrast to P. berghei single-infected animals, Filaria-infected mice had significantly higher levels of circulating IL-10. The requirement for IL-10 in CM protection was demonstrated by the lack of protection in IL-10 KO mice. This suggests that the anti-inflammatory IL-10 elicited by Filarial nematodes is able to suppress the overwhelming inflammatory reaction otherwise triggered against malaria parasites in C57BL/6 mice, preventing full progress to CM.
-
reliable and frequent detection of adult wuchereria bancrofti in ghanaian women by ultrasonography
2004Co-Authors: Sabine Mand, Linda Batsa, Alexander Yaw Debrah, Ohene Adjei, Achim HoeraufAbstract:Detection of adult Wuchereria bancrofti by ultrasonography of the scrotal region in men is a suitable diagnostic tool for lymphatic Filariasis, whereas there are only a few case reports of adult Filariae observed by ultrasonography in women. We examined 35 microfilaraemic women ultrasonographically in sites of the body suspected as locations for worm nests. In 15 women the 'Filaria dance sign' (FDS) was detected in various locations, some being novel, such as adult worms within lymphatic vessels between muscular fibres of the thighs. The surprisingly high number of worm nests detectable in microfilaraemic women recommends ultrasonography for diagnosis and treatment efficacy monitoring of female patients infected with W. bancrofti.
-
neutrophil accumulation around onchocerca worms and chemotaxis of neutrophils are dependent on wolbachia endobacteria
2001Co-Authors: Norbert W Brattig, Dietrich W Büttner, Achim HoeraufAbstract:Unlike in many other helminth infections, neutrophilic granulocytes are major cellular components in the host's immune response against Filarial worms. The pathways that drive the immune response involving neutrophils are unclear. This study shows that Wolbachia endobacteria (detectable by polyclonal antibodies against endobacterial heat shock protein 60 and catalase and by polymerase chain reaction being sensitive to doxycycline treatment) are direct and indirect sources of signals accounting for neutrophil accumulation around adult Onchocerca volvulus Filariae. Worm nodules from untreated onchocerciasis patients displayed a strong neutrophil infiltrate adjacent to the live adult worms. In contrast, in patients treated with doxycycline to eliminate the endobacteria from O. volvulus and to render the worms sterile, the neutrophil accumulation around live adult Filariae was drastically reduced. Neutrophils were absent in worm nodules from the deer Filaria Onchocerca flexuosa, a species which does not contain endobacteria. Extracts of O. volvulus extirpated from untreated patients showed neutrophil chemotactic activity and in addition, induced strong TNF-α and IL-8 production in human monocytes, in contrast to Filarial extracts obtained after doxycycline treatment. Thus, neutrophil chemotaxis and activation are induced directly by endobacterial products and also indirectly via chemokine induction by monocytes. These results show that the neutrophil response is a characteristic of endobacteria-containing Filariae. © 2001 Editions scientifiques et medicales Elsevier SAS
Thomas B. Nutman - One of the best experts on this subject based on the ideXlab platform.
-
interferon regulatory factor modulation underlies the bystander suppression of malaria antigen driven il 12 and ifn γ in Filaria malaria co infection
2012Co-Authors: Simon Metenou, Benoit Dembele, Amy D Klion, Michael A Kovacs, Yaya I Coulibaly, Thomas B. NutmanAbstract:In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-γ, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12Rβ1, IL-12Rβ2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 Filaria-infected (Fil(+)) and 17 Filaria-uninfected (Fil(-)) individuals in a Filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12Rβ1 or IL-12Rβ2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microFilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microFilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in Filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria.
-
functional and phenotypic characteristics of alternative activation induced in human monocytes by interleukin 4 or the parasitic nematode brugia malayi
2011Co-Authors: Roshanak Tolouei Semnani, Lily Mahapatra, Vanessa Moore, Vivornpun Sanprasert, Thomas B. NutmanAbstract:Human monocytes from patients with patent Filarial infections are studded with Filarial antigen and express markers associated with alternative activation of macrophages (MΦ). To explore the role of Filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microFilariae (mf) of Brugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 [IL-4]) or classically (macrophage colony-stimulating factor [MCSF]) activated MΦ. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦ but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4+ and CD8+ T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. In contrast to results with MCSF-cultured monocytes, exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted Filarial products skew monocytes similarly.
-
cd4 and not cd25 t cells are the predominant interleukin 10 producing cells in the circulation of Filaria infected patients
2008Co-Authors: Edward Mitre, Daniel Chien, Thomas B. NutmanAbstract:BACKGROUND Interleukin (IL)-10 plays an important role in down-regulating the immune response to Filarial parasites. The goal of this study was to characterize the predominant cellular source of IL-10 in human Filarial infections. METHODS Multicolor flow cytometry was used to determine the frequencies of IL-10 production from various lymphocyte populations in the circulation of 23 patients with Filarial infections and 8 uninfected control subjects. RESULTS The frequencies of cells spontaneously producing IL-10 was significantly greater in Filaria-infected patients than in uninfected control subjects (geometric mean, 93 vs. 18 IL-10-producing cells/100,000 peripheral blood mononuclear cells; P = .03). Most IL-10-producing cells in Filaria-infected patients were T cells, with CD4(+) and CD8(+) cells accounting for 48% and 27%, respectively, of all IL-10-producing cells; CD19(+) B cells, CD14(+) monocytes, and CD56(+) NK cells accounted for 10%, 8%, and 7%, respectively. Surprisingly, only 12% of the IL-10-producing CD3(+)CD4(+) cells were CD25(+). Seventy-seven percent of IL-10-producing CD4(+) T cells stained negatively for both IL-4 and interferon (IFN)-gamma, 22% were positive for IL-4, and <1% were positive for IFN-gamma. CONCLUSIONS These experiments demonstrate that the most frequent producers of IL-10 in human Filarial infections are CD4(+) T cells, many of which are skewed toward a type 2 phenotype and most of which are not CD25(+).
-
Filariasis in travelers presenting to the geosentinel surveillance network
2007Co-Authors: Ettie M Lipner, Melissa A Law, Elizabeth D Barnett, Jay S Keystone, Frank Von Sonnenburg, Louis Loutan, Rebecca D Prevots, Amy D Klion, Thomas B. NutmanAbstract:Background: As international travel increases, there is rising exposure to many pathogens not traditionally encountered in the resource-rich countries of the world. Filarial infections, a great problem throughout the tropics and subtropics, are relatively rare among travelers even to Filaria-endemic regions of the world. The GeoSentinel Surveillance Network, a global network of medicine/travel clinics, was established in 1995 to detect morbidity trends among travelers. Principal Findings: We examined data from the GeoSentinel database to determine demographic and travel characteristics associated with Filaria acquisition and to understand the differences in clinical presentation between nonendemic visitors and those born in Filaria-endemic regions of the world. Filarial infections comprised 0.62% (n = 271) of all medical conditions reported to the GeoSentinel Network from travelers; 37% of patients were diagnosed with Onchocerca volvulus, 25% were infected with Loa loa, and another 25% were diagnosed with Wuchereria bancrofti. Most infections were reported from immigrants and from those immigrants returning to their county of origin ( those visiting friends and relatives); the majority of Filarial infections were acquired in sub-Saharan Africa. Among the patients who were natives of Filaria-nonendemic regions, 70.6% acquired their Filarial infection with exposure greater than 1 month. Moreover, nonendemic visitors to Filaria-endemic regions were more likely to present to GeoSentinel sites with clinically symptomatic conditions compared with those who had lifelong exposure. Significance: Codifying the Filarial infections presenting to the GeoSentinel Surveillance Network has provided insights into the clinical differences seen among Filaria-infected expatriates and those from endemic regions and demonstrated that O. volvulus infection can be acquired with short-term travel.
-
diminished expression and function of tlr in lymphatic Filariasis a novel mechanism of immune dysregulation
2005Co-Authors: Subash Babu, Carla P Blauvelt, V Kumaraswami, Thomas B. NutmanAbstract:Lymphatic Filariasis is a disease characterized by immune dysregulation involving APC and T cell populations. To assess the contribution of TLR in mediating this dysregulation, we examined the expression of TLR1, TLR2, TLR4, and TLR9 on B cells and monocytes of Filaria-infected and uninfected individuals. Baseline expression of TLR was significantly lower in B cells but not in monocytes of the Filaria-infected group compared with the uninfected group. Upon stimulation with Filarial Ag, a diminished up-regulation of TLR was observed in both B cells and monocytes of infected individuals. Finally, stimulation of B cells and monocytes with TLR ligands resulted in decreased B cell and monocyte activation/cytokine production, indicating a state of immune tolerance. This dysregulation is associated with diminished CD4 + T cell production of IFN-γ and IL-5. The diminished expression and function of TLR is thus a likely consequence of chronic Ag stimulation and could serve as a novel mechanism underlying the dysfunctional immune response in Filariasis.
Amy G. Hise - One of the best experts on this subject based on the ideXlab platform.
-
Filaria wolbachia activation of dendritic cells and development of th1 associated responses is dependent on toll like receptor 2 in a mouse model of ocular onchocerciasis river blindness
2007Co-Authors: Katrin Daehnel, Illona Gilletteferguson, Amy G. Hise, Eugenia Diaconu, M J Harling, Fred P Heinzel, Eric PearlmanAbstract:Toll-like receptors (TLRs) regulate dendritic cell function and activate signals that mediate the nature of the adaptive immune response. The current study examined the role of TLRs in dendritic cell activation and in regulating T cell and antibody responses to antigens from the Filarial parasites Onchocerca volvulus and Brugia malayi, which cause river blindness and lymphatic Filariasis, respectively. Bone-marrow-derived CD11c(+) cells from C57BL/6 and TLR4(-/-) mice produced high levels of IL-6 and RANTES, and showed elevated surface CD40 expression, whereas CD11c(+) cells from myeloid differentiation factor 88(-/-) (MyD88(-/-)), TLR2(-/-) and TLR2/4(-/-) mice were not activated. Similarly, IFN-gamma production by splenocytes from immunized TLR2(-/-) mice was significantly impaired compared with splenocytes from C57BL/6 and TLR4(-/-) mice. In contrast, there was no difference among these strains in Th2-associated responses including IL-5 production by splenocytes from immunized animals, serum IgE and IgG(1), or eosinophil infiltration into the corneal stroma. Neutrophil recruitment to the cornea and CXC chemokine production was inhibited in immunized TLR2(-/-) mice compared with C57BL/6 and TLR4(-/-) mice. Taken together, these findings demonstrate an essential role for TLR2 in Filaria-induced dendritic cell activation, IFN-gamma production and neutrophil migration to the cornea, but does not affect Filaria-induced Th2-associated responses.
-
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
2007Co-Authors: Amy G. Hise, Illona Gilletteferguson, Helen F Mcgarry, Katrin Daehnel, James W Kazura, Mark J. Taylor, Katherine A Fitzgerald, Douglas T Golenbock, Eric PearlmanAbstract: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.
-
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
2007Co-Authors: Amy G. Hise, Illona Gilletteferguson, Helen F Mcgarry, Katrin Daehnel, James W Kazura, Mark J. Taylor, Katherine A Fitzgerald, Douglas T Golenbock, Eun Wie Cho, Eric PearlmanAbstract: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.
Claudio Bandi - One of the best experts on this subject based on the ideXlab platform.
-
the bacterial catalase from Filarial dna preparations derives from common pseudomonad contaminants and not from wolbachia endosymbionts
2004Co-Authors: Jeremy M Foster, Mark Blaxter, Barton E. Slatko, Laura Baldo, Kimberly Henkleduhrsen, Claire Whitton, Claudio BandiAbstract:Wolbachia are obligatory endosymbionts in many species of Filarial nematodes. Certain bacterial molecules induce antibody responses in mammalian hosts infected with Filariae, while others activate inflammatory responses that contribute to pathology. These findings, coupled with antibiotic studies demonstrating the dependence of Filarial embryogenesis on the presence of Wolbachia, have intensified research on Wolbachia-nematode interactions, and the effects of Wolbachia molecules on the mammalian immune system. By amplification and sequencing of 16S rDNA and catalase sequences, we show that Filarial DNA samples prepared from nematodes collected under typical conditions are frequently contaminated with Pseudomonas DNA. Analysis of a published DNA fragment containing a catalase attributed to the Wolbachia of Onchocerca volvulus showed it to be most like Pseudomonas, both in terms of sequence similarity and genomic organization. Additionally, there was no obvious catalase in either of two available Wolbachia genome sequences. Contamination of Filarial DNA with bacterial sequences other than Wolbachia can complicate studies of the role of these symbionts in Filarial biology.
-
mapping the presence of wolbachia pipientis on the phylogeny of Filarial nematodes evidence for symbiont loss during evolution
2004Co-Authors: Maurizio Casiraghi, C. Martin, Ricardo Guerrero, O Bain, Vanessa Pocacqua, Scott Lyell Gardner, A Franceschi, Claudio BandiAbstract:Wolbachia pipientis is a bacterial endosymbiont associated with arthropods and Filarial nematodes. In Filarial nematodes, W. pipientis has been shown to play an important role in the biology of the host and in the immuno-pathology of Filariasis. Several species of Filariae, including the most important parasites of humans and animals (e.g. Onchocerca volvulus, Wuchereria bancrofti and DiroFilaria immitis) have been shown to harbour these bacteria. Other Filarial species, including an important rodent species (Acanthocheilonema viteae), which has been used as a model for the study of Filariasis, do not appear to harbour these symbionts. There are still several open questions about the distribution of W. pipientis in Filarial nematodes. Firstly the number of species examined is still limited. Secondly, it is not clear whether the absence of W. pipientis in negative species could represent an ancestral characteristic or the result of a secondary loss. Thirdly, several aspects of the phylogeny of Filarial nematodes are still unclear and it is thus difficult to overlay the presence/absence of W. pipientis on a tree representing Filarial evolution. Here we present the results of a PCR screening for W. pipientis in 16 species of Filariae and related nematodes, representing different families/subfamilies. Evidence for the presence of W. pipientis is reported for five species examined for the first time (representing the genera Litomosoides, Litomosa and Dipetalonema); original results on the absence of this bacterium are reported for nine species; for the remaining two species, we have confirmed the absence of W. pipientis recently reported by other authors. In the positive species, the infecting W. pipientis bacteria have been identified through 16S rDNA gene sequence analysis. In addition to the screening for W. pipientis in 16 species, we have generated phylogenetic reconstructions based on mitochondrial gene sequences (12S rDNA; COI), including a total of 28 Filarial species and related spirurid nematodes. The mapping of the presence/absence of W. pipientis on the trees generated indicates that these bacteria have possibly been lost during evolution along some lineages of Filarial nematodes.
-
tetracycline treatment and sex ratio distortion a role for wolbachia in the moulting of Filarial nematodes
2002Co-Authors: Maurizio Casiraghi, C Genchi, John W Mccall, L Simoncini, L H Kramer, L Sacchi, John H Werren, Claudio BandiAbstract:Abstract Filarial nematodes harbour intracellular bacteria of the genus Wolbachia. These bacteria are thought to be beneficial to the host nematode. Indeed, tetracycline treatments reduce the population of Wolbachia in Filarial worms and have detrimental effects on the nematode. Even though various antibiotic-curing experiments have been performed on Filariae, the actual role of Wolbachia in the biology of these nematodes is not yet clear. To address this issue, we designed a first experiment on a model Filaria (Brugia pahangi), maintained in the gerbil (Meriones unguiculatus). In this experiment, timing of tetracycline treatment was set on the basis of the larval stage of the nematode. This first experiment showed that 2 weeks of treatment started after the L4–L5 moult of males, but before the moult of females, led to significant sex-ratio distortion of the nematodes. We thus hypothesised that tetracycline interferes with the moult in B. pahangi. To test this hypothesis, we designed a second experiment in which antibiotic treatments were started (1) before the moult of both sexes, (2) after the moult of males but before the moult of females, or (3) after the moult of both sexes. Treatment 1 determined a reduction of worm recovery with no sex bias. Treatment 2 led to a male-biased sex-ratio. Treatment 3 had no effect on either worm recovery or sex-ratio. These results thus support the hypothesis that tetracycline treatment interferes with the L4–L5 moult of B. pahangi. The nematodes recovered from the treated and control animals were examined for the presence of Wolbachia using both immunohistochemistry and real-time PCR. In general, nematodes from treated animals showed a dramatic reduction in Wolbachia content. In one group, Wolbachia depletion, as observed at the end of the treatment, was followed by a rebound to ‘normal’ values 160 days later. Prospects for antiFilarial therapy using Wolbachia-targeted tetracycline treatments should thus take into account the possibility of Wolbachia rebound.
-
a phylogenetic analysis of Filarial nematodes comparison with the phylogeny of wolbachia endosymbionts
2001Co-Authors: Maurizio Casiraghi, Claudio Bandi, Timothy J C Anderson, C Bazzocchi, C GenchiAbstract:Infection with the endosymbiotic bacteria Wolbachia is widespread in Filarial nematodes. Previous studies have suggested concordance between the phylogeny of Wolbachia with that of their nematode hosts. However, there is only one published molecular phylogenetic study of Filarial species, based on the 5S rRNA gene spacer. The phylogeny proposed by this study is partially incongruent with previous classifications of Filarial nematodes, based on morphological characters. Furthermore, both traditional classifications and molecular phylogenies are, in part, inconsistent with the phylogeny of Wolbachia. Here we report mitochondrial cytochrome oxidase I (COI) gene sequences for 11 species of Filaria and for another spirurid nematode which was included as an outgroup. In addition, 16S rRNA, wsp and ftsZ gene sequences were generated for the Wolbachia of several Filarial species, in order to complete the available data sets and further resolve the phylogeny of Wolbachia in nematodes. We used these data to evaluate whether nematode and Wolbachia phylogenies are concordant. Some of the possible phylogenetic reconstructions based on COI gene were congruent with the phylogeny of Wolbachia and supported the grouping of the rodent Filaria Litomosoides sigmodontis with the lymphatic Filariae (i.e. Brugia spp. and Wuchereria spp.) and the sister group relationship of DiroFilaria spp. and Onchocerca spp. However, the placement of the Wolbachia-free Filaria Acanthocheilonema viteae is ambiguous and dependent on the phylogenetic methods used.