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1.
PLoS Pathog ; 15(9): e1008085, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31568486

RESUMEN

Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.


Asunto(s)
Brugia/metabolismo , Brugia/microbiología , Ácido Pirúvico/metabolismo , Wolbachia/metabolismo , Animales , Brugia/genética , Brugia Malayi/genética , Brugia Malayi/metabolismo , Brugia Malayi/microbiología , Brugia pahangi/genética , Brugia pahangi/metabolismo , Brugia pahangi/microbiología , Femenino , Filariasis/metabolismo , Filariasis/microbiología , Filariasis/parasitología , Genes de Helminto , Glucólisis , Interacciones Microbiota-Huesped , Interacciones Huésped-Parásitos , Humanos , Masculino , Simbiosis , Wolbachia/genética
2.
Infect Immun ; 85(1)2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27799335

RESUMEN

Filarial parasites cause functional impairment of host dendritic cells (DCs). However, the effects of early infection on individual DC subsets are not known. In this study, we infected BALB/c mice with infective stage 3 larvae of the lymphatic filarial parasite Brugia malayi (Bm-L3) and studied the effect on fluorescence-activated cell sorter (FACS)-sorted DC subsets. While myeloid DCs (mDCs) accumulated by day 3 postinfection (p.i.), lymphoid DCs (LDCs) and CD8+ plasmacytoid DCs (pDCs) peaked at day 7 p.i. in the spleens and mesenteric lymph nodes (mLNs) of infected mice. Increased tumor necrosis factor alpha (TNF-α) but reduced interleukin 12 (IL-12) and Toll-like receptor 4 (TLR4), -6, and -9 and reciprocal secretion of IL-4 and IL-10 were also observed across all DC subsets. Interestingly, Bm-L3 increased the expression of CD80 and CD86 across all DC subsets but decreased that of major histocompatibility complex class II (MHC-II) on mDCs and pDCs, resulting in their impaired antigen uptake and presentation capacities, but maximally attenuated the T-cell proliferation capacity of only mDCs. Furthermore, Bm-L3 increased phosphorylated p38 (p-p38), but not p-ERK, in mDCs and LDCs but downregulated them in pDCs, along with differential modulation of protein tyrosine phosphatases SHP-1, TCPTP, PTEN, and PTP1B across all DC subsets. Taken together, we report hitherto undocumented effects of early Bm-L3 infection on purified host DC subsets that lead to their functional impairment and attenuated host T-cell response.


Asunto(s)
Brugia Malayi/patogenicidad , Células Dendríticas/patología , Células Dendríticas/parasitología , Filariasis/patología , Filariasis/parasitología , Larva/parasitología , Animales , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/fisiología , Células Dendríticas/metabolismo , Regulación hacia Abajo/fisiología , Filariasis/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Activación de Linfocitos/fisiología , Ratones , Ratones Endogámicos BALB C , Fosfohidrolasa PTEN/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
3.
J Infect Dis ; 213(5): 811-5, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26486636

RESUMEN

Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae-infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL-19 and IL-24 are associated with the modulation of T-cell responses in filarial infections.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Filariasis/metabolismo , Interleucinas/metabolismo , Filariasis/inmunología , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucinas/genética , Subgrupos de Linfocitos T
4.
Parasite Immunol ; 36(2): 60-77, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24112106

RESUMEN

Eosinophil migration as key feature of helminth infection is increased during infection with filarial nematodes. In a mouse model of filariasis, we investigated the role of the eosinophil-attracting chemokine Eotaxin-1 on disease outcome. BALB/c and Eotaxin-1(-/-) mice were infected with the rodent filaria Litomosoides sigmodontis, and parasitic parameters, cellular migration to the site of infection, and cellular responsiveness were investigated. We found increased parasite survival but unaffected eosinophil migration to the site of infection in Eotaxin-1(-/-) mice. Expression of CD80 and CD86 was reduced on eosinophils from Eotaxin-1(-/-) mice after in vitro TLR2 stimulation and exposure to filarial antigen, respectively, suggesting a potential reduced activation state of eosinophils in Eotaxin-1 deficient mice. We further demonstrated that macrophages from Eotaxin-1(-/-) mice produce decreased amounts of IL-6 in vitro, a cytokine found to be associated with parasite containment, suggesting possible mechanisms by which Eotaxin-1 regulates activation of inflammatory cells and thus parasite survival.


Asunto(s)
Quimiocina CCL11/fisiología , Eosinófilos/inmunología , Filariasis/inmunología , Filarioidea/inmunología , Macrófagos/inmunología , Animales , Presentación de Antígeno , Antígenos Helmínticos/inmunología , Movimiento Celular , Células Cultivadas , Quimiocina CCL11/deficiencia , Quimiocina CCL11/genética , Quimiocina CCL24/metabolismo , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Eosinófilos/fisiología , Células Epiteliales/metabolismo , Femenino , Filariasis/metabolismo , Filariasis/parasitología , Filarioidea/crecimiento & desarrollo , Interleucina-6/metabolismo , Activación de Macrófagos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Microfilarias/fisiología , Carga de Parásitos , Cavidad Pleural/inmunología , Cavidad Pleural/parasitología , Bazo/inmunología
5.
J Immunol ; 188(9): 4188-99, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22461700

RESUMEN

Basophils play a key role in the development and effector phases of type 2 immune responses in both allergic diseases and helminth infections. This study shows that basophils become less responsive to IgE-mediated stimulation when mice are chronically infected with Litomosoides sigmodontis, a filarial nematode, and Schistosoma mansoni, a blood fluke. Although excretory/secretory products from microfilariae of L. sigmodontis suppressed basophils in vitro, transfer of microfilariae into mice did not result in basophil suppression. Rather, reduced basophil responsiveness, which required the presence of live helminths, was found to be dependent on host IL-10 and was accompanied by decreases in key IgE signaling molecules known to be downregulated by IL-10. Given the importance of basophils in the development of type 2 immune responses, these findings help explain the mechanism by which helminths protect against allergy and may have broad implications for understanding how helminth infections alter other disease states in people.


Asunto(s)
Basófilos/inmunología , Filariasis/inmunología , Filarioidea/inmunología , Interleucina-10/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Animales , Basófilos/metabolismo , Enfermedad Crónica , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Filariasis/genética , Filariasis/metabolismo , Filarioidea/metabolismo , Inmunoglobulina E/genética , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Schistosoma mansoni/metabolismo , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Células Th2/inmunología , Células Th2/metabolismo
6.
J Immunol ; 188(2): 559-68, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22174447

RESUMEN

Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-ß alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4-deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4-deficient NOD mice were accompanied by increases in CD4(+)CD25(+)Foxp3(+) regulatory T cell frequencies and numbers, respectively, and helminth infection increased the proliferation of CD4(+)Foxp3(+) cells. However, depletion of CD25(+) cells in NOD mice or Foxp3(+) T cells from splenocytes transferred into NOD.scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGF-ß, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity, because helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-ß.


Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Diabetes Mellitus Tipo 1/parasitología , Filariasis/inmunología , Filariasis/parasitología , Filarioidea/inmunología , Células TH1/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Filariasis/metabolismo , Interleucina-10/biosíntesis , Interleucina-10/fisiología , Interleucina-4/deficiencia , Interleucina-4/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos NOD , Ratones Noqueados , Ratones Transgénicos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/parasitología , Linfocitos T Reguladores/patología , Células TH1/metabolismo , Células TH1/parasitología , Factor de Crecimiento Transformador beta/fisiología
7.
Front Immunol ; 12: 714052, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34603287

RESUMEN

The T cell immune responses in filarial infections are primarily mediated by CD4+ T cells and type 2-associated cytokines. Emerging evidence indicates that CD8+ T cell responses are important for anti-filarial immunity, however, could be suppressed in co-infections. This review summarizes what we know so far about the activities of CD8+ T cell responses in filarial infections, co-infections, and the associations with the development of filarial pathologies.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Susceptibilidad a Enfermedades/inmunología , Filariasis/etiología , Filariasis/metabolismo , Interacciones Huésped-Parásitos/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Biomarcadores , Coinfección , Citocinas/metabolismo , Modelos Animales de Enfermedad , Filariasis/prevención & control , Humanos , Inmunomodulación , Vacunas/inmunología
8.
J Immunol ; 181(9): 6456-66, 2008 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-18941236

RESUMEN

Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system's failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25(+)Foxp3(+) cells within the CD4(+) T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3(-) cells, suggesting anergized effector populations. Peritoneal lavage CD4(+)CD25(+) cells from infected mice showed similar suppressive activity in vitro to normal splenic "natural" Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.


Asunto(s)
Brugia Malayi/inmunología , Factores de Transcripción Forkhead/biosíntesis , Activación de Linfocitos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/parasitología , Traslado Adoptivo , Animales , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Filariasis/inmunología , Filariasis/metabolismo , Filariasis/patología , Gerbillinae , Humanos , Activación de Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Receptores de Interleucina-4/deficiencia , Receptores de Interleucina-4/genética , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/trasplante
9.
Dev Cell ; 45(2): 198-211.e3, 2018 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-29689195

RESUMEN

Although symbiotic interactions are ubiquitous in the living world, examples of developmental symbioses are still scarce. We show here the crucial role of Wolbachia in the oogenesis of filarial nematodes, a class of parasites of biomedical and veterinary relevance. We applied newly developed techniques to demonstrate the earliest requirements of Wolbachia in the parasite germline preceding the production of faulty embryos in Wolbachia-depleted nematodes. We show that Wolbachia stimulate germline proliferation in a cell-autonomous manner, and not through nucleotide supplementation as previously hypothesized. We also found Wolbachia to maintain the quiescence of a pool of germline stem cells to ensure a constant delivery of about 1,400 eggs per day for many years. The loss of quiescence upon Wolbachia depletion as well as the disorganization of the distal germline suggest that Wolbachia are required to execute the proper germline stem cell developmental program in order to produce viable eggs and embryos.


Asunto(s)
Brugia Malayi/crecimiento & desarrollo , Filariasis/patología , Células Germinativas/citología , Proteínas del Helminto/metabolismo , Células Madre/fisiología , Simbiosis , Wolbachia/fisiología , Animales , Brugia Malayi/microbiología , Proliferación Celular , Femenino , Filariasis/metabolismo , Filariasis/parasitología , Células Germinativas/microbiología , Células Germinativas/fisiología , Proteínas del Helminto/genética , Masculino , Células Madre/citología , Células Madre/microbiología
10.
PLoS One ; 12(11): e0188138, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29141050

RESUMEN

Parasitic nematodes have evolved powerful immunomodulatory molecules to enable their survival in immunocompetent hosts by subverting immune responses and minimizing pathological processes. One filarial molecule known to counteract host immune responses by inducing IL-10 and regulatory macrophages in mice is filarial cystatin. During a patent filarial infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. The microfilarial larval stage was formerly shown to induce human regulatory monocytes and macrophages. Thus, here we aim was to determine how filarial cystatin of the human pathogenic filaria Brugia malayi (BmCPI-2) contributes to immune hyporesponsiveness in human monocytes and macrophages elicited by microfilaria. For this purpose, filarial cystatin was depleted from microfilarial lysate (Mf). Detecting the immunomodulatory potential of cystatin-depleted Mf revealed that IL-10, but not IL-8 and IL-6 induction in monocytes and macrophages is dependent on the presence of cystatin. In addition, the Mf-induced expression of the regulatory surface markers PD-L1 and PD-L2 in human monocytes, but not in macrophages, is dependent on cystatin. While Mf-treated monocytes result in decreased CD4+ T-cell proliferation in a co-culture assay, stimulation of T-cells with human monocytes treated with cystatin-depleted Mf lead to a restoration of CD4+ T-cell proliferation. Moreover, IL-10 induction by cystatin within Mf was dependent on p38 and ERK in macrophages, but independent of the ERK pathway in monocytes. These findings indicate that filarial nematodes differentially trigger and exploit various signaling pathways to induce immunomodulation in different myeloid cell subsets.


Asunto(s)
Brugia Malayi/metabolismo , Cistatinas/farmacología , Filariasis/metabolismo , Macrófagos/inmunología , Monocitos/inmunología , Animales , Antígeno B7-H1/metabolismo , Interacciones Huésped-Parásitos , Humanos , Interleucinas/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo
11.
Int J Parasitol ; 47(14): 903-912, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28743489

RESUMEN

Onchocerciasis, a neglected tropical disease prevalent in western and central Africa, is a major health problem and has been targeted for elimination. The causative agent for this disease is the human parasite Onchocerca volvulus. Onchocerca ochengi and Litomosoides sigmodontis, infectious agents of cattle and rodents, respectively, serve as model organisms to study filarial nematode infections. Biomarkers to determine infection without the use of painful skin biopsies and microscopic identification of larval worms are needed and their discovery is facilitated by an improved knowledge of parasite-specific metabolites. In addition to proteins and nucleic acids, lipids may be suitable candidates for filarial biomarkers that are currently underexplored. To fill this gap, we present the phospholipid profile of the filarial nematodes O. ochengi, O. volvulus and L. sigmodontis. Direct infusion quadrupole time-of-flight (Q-TOF) mass spectrometry was employed to analyze the composition of phospholipids and their molecular species in the three nematode species. Analysis of the phospholipid profiles of plasma or serum of uninfected and infected hosts showed that nematode-specific phospholipids were below detection limits. However, several phospholipids, in particular ether lipids of phosphatidylethanolamine (PE), were abundant in O. ochengi worms and in bovine nodule fluid, suggesting that these phospholipids might be released from O. ochengi into the host, and could serve as potential biomarkers.


Asunto(s)
Filariasis/metabolismo , Filarioidea/metabolismo , Onchocerca/metabolismo , Oncocercosis/metabolismo , Éteres Fosfolípidos/metabolismo , Animales , Biomarcadores/metabolismo , Bovinos , Femenino , Gerbillinae , Humanos , Masculino , Onchocerca volvulus/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem
12.
Invest Ophthalmol Vis Sci ; 43(8): 2677-84, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12147602

RESUMEN

PURPOSE: Calgranulin C (CaGC) is a protein released by activated neutrophils and involved in host defense against filarial infections. This study involved the identification of binding protein(s) of the helminth Brugia malayi to CaGC and the ability of binding complexes to induce keratitis. METHODS: Parasitic extracts prepared from B. malayi microfilariae and adult worms were incubated with recombinant CaGC protein. Parasite binding protein-CaGC complex was isolated by affinity chromatography. A B. malayi microfilariae cDNA library was immunoscreened with antisera from rats immunized with the isolated parasitic CaGC-binding protein. All positive clones contained paramyosin sequences. Paramyosin was thus considered the major CaGC-binding protein in the parasite. To delineate the binding of CaGC to native and recombinant paramyosin, 125I-CaGC was used as a binding tracer in SDS-PAGE analysis to identify a CaGC-binding complex. To determine whether the complex of CaGC and its binding protein could induce keratitis mimicking the onchocercal human corneal disease, BALB/c mice preimmunized with the binding complex were challenged with intracorneal binding complex or live Brugia microfilariae. In addition, splenocytes harvested from the same animals were assessed for their ability to elicit cellular immune responses to the binding complex by [3H]thymidine assay. RESULTS: In vitro binding of CaGC to paramyosin was confirmed using recombinant paramyosin and 125I-CaGC. Test animals showed development of severe keratitis that mimicked, clinically and histopathologically, the human onchocercal corneal disease, demonstrating the antigenic specificity of the paramyosin-CaGG-binding complex. CONCLUSIONS: Paramyosin is identified as a CaGC-binding protein in B. malayi.


Asunto(s)
Brugia Malayi/fisiología , Infecciones Parasitarias del Ojo/metabolismo , Filariasis/metabolismo , Queratitis/metabolismo , Proteínas Protozoarias/metabolismo , Proteínas S100/metabolismo , Tropomiosina/metabolismo , Animales , Cromatografía de Afinidad , Electroforesis en Gel de Poliacrilamida , Infecciones Parasitarias del Ojo/parasitología , Infecciones Parasitarias del Ojo/patología , Femenino , Filariasis/parasitología , Filariasis/patología , Inmunidad Celular , Inmunización , Queratitis/parasitología , Queratitis/patología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Proteínas Protozoarias/inmunología , Ratas , Ratas Endogámicas Lew , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes , Proteínas S100/inmunología , Proteína S100A12 , Tropomiosina/inmunología
13.
Am J Trop Med Hyg ; 62(1): 86-91, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10761730

RESUMEN

The pharmacokinetics of the filaricidal benzimidazole compounds UMF-078 and UMF-289 were evaluated in beagle dogs experimentally infected with Brugia pahangi. Twenty-four infected microfilaremic beagles were selected and randomly allocated into 4 treatment groups of 6 dogs each: oral (PO) UMF-078, PO UMF-289 (the HCl salt form of UMF-078), intramuscular (IM) UMF-078, and untreated controls. Equivalent doses of 50 mg/kg of the free base were given twice a day for 3 days to the 3 groups of treated dogs. Oral absorption is rapid compared with IM dosing; the absorption half-life (K01-HL) for the IM treatment is approximately 14 hr compared with 1 and 2 hr for the PO regimen of salt and free base forms, respectively. The elimination half-lives (K10-HL) for the PO regimens are 13 and 15 hr for the salt and free base forms, respectively. Because of sustained absorption following IM dosing, the K10-HL is prolonged. In contrast to oral administration, IM dosing of UMF-078 provides sustained, relatively low plasma drug levels, with good tolerance and efficacy.


Asunto(s)
Antinematodos/farmacocinética , Brugia pahangi/efectos de los fármacos , Filariasis/tratamiento farmacológico , Mebendazol/análogos & derivados , Administración Oral , Animales , Antinematodos/administración & dosificación , Antinematodos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Perros , Femenino , Filariasis/metabolismo , Semivida , Inyecciones Intramusculares , Masculino , Mebendazol/administración & dosificación , Mebendazol/sangre , Mebendazol/farmacocinética , Distribución Aleatoria
14.
Am J Trop Med Hyg ; 58(6): 695-704, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9660448

RESUMEN

Brugia pahangi infection in the canine rear limb results in marked lymphatic duct and popliteal lymph node pathologic changes. Limb edema is variably associated with infection and does not correlate well with duct or node lesions. To understand the mechanisms of limb edema, lymph node cells were collected by sequential biopsy following infection and examined for production of inflammatory mediators. Lymph node cells from a litter of dogs selectively bred with a high incidence of edema formation (82%) demonstrated spontaneously released histamine and prostaglandin E2 levels higher than those of closely related nonedema-forming dogs (0-20%) and/or control dogs. These edema-forming dogs also showed elevated release of tumor necrosis factor-alpha when cells were cultured with Brugia antigen. Toluidine blue staining of infected lymph node sections revealed that the edema-forming dogs had higher numbers of mast cells than infected lymph nodes of nonedema-forming dogs.


Asunto(s)
Brugia pahangi , Enfermedades de los Perros/genética , Filariasis/veterinaria , Histamina/metabolismo , Ganglios Linfáticos/metabolismo , Linfedema/veterinaria , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Biopsia/veterinaria , Brugia pahangi/fisiología , Células Cultivadas , Dinoprostona/metabolismo , Enfermedades de los Perros/etiología , Enfermedades de los Perros/metabolismo , Perros , Femenino , Filariasis/complicaciones , Filariasis/metabolismo , Inmunohistoquímica , Ganglios Linfáticos/patología , Linfedema/etiología , Linfedema/genética , Activación de Linfocitos , Masculino , Linaje
15.
Acta Trop ; 46(4): 249-56, 1989 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2571252

RESUMEN

Possible endocrinological repercussions of infection with Loa loa and Mansonella perstans filariae were studied in Gabonese subjects. Microfilaremic males were compared with amicrofilaremic controls. In the infected group 13/105 subjects (12%) presented only abnormally low serum levels of testosterone (less than 4 ng/ml), 25/105 (24%) only abnormally high serum levels of gonadotrophins, FSH (greater than 15 mIU/ml) and LH (greater than 20 mIU/ml), and 22/105 (21%) presented anomalies in both testosterone and gonadotrophin levels. One out of 68 control subjects had 3.6 ng/ml seric testosterone and all had normal levels of gonadotrophins. Ecdysteroids were detected (greater than 0.025 ng/ml) in the serum of 87/97 (90%) microfilaremic subjects (GM 0.123 ng/ml) compared to 12/64 (19%) controls (GM 0.030 ng/ml). Ecdysteroids were detected in the urine of all subjects, infected (GM 8.468 ng/ml) as well as control (GM 1.245 ng/ml). The hormonal perturbations were correlated with the levels of Loa loa microfilaremia but not with those of serum and urinary ecdysteroids. These results demonstrate that microfilaremic subjects often show endocrinal signs of hypogonadism and present appreciable levels of ecdysteroids in serum and urine. A direct role for parasitic ecdysteroids in hypogonadism remains to be demonstrated.


Asunto(s)
Filariasis/metabolismo , Hipogonadismo/etiología , Hormonas de Invertebrados/biosíntesis , Loiasis/metabolismo , Mansoneliasis/metabolismo , Adulto , Animales , Ecdisteroides , Hormona Folículo Estimulante/sangre , Humanos , Hipogonadismo/metabolismo , Hormonas de Invertebrados/sangre , Hormonas de Invertebrados/orina , Loa/aislamiento & purificación , Loiasis/complicaciones , Hormona Luteinizante/sangre , Masculino , Mansonella/aislamiento & purificación , Mansoneliasis/complicaciones , Microfilarias/aislamiento & purificación , Persona de Mediana Edad , Testosterona/sangre
16.
Magn Reson Imaging ; 17(10): 1503-9, 1999 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-10609999

RESUMEN

Metabolite mapping of human filarial parasite, Brugia malayi was carried out in vitro as well as in situ in host Mastomys coucha by 31P nuclear magnetic resonance (NMR) spectroscopy. Detection of parasites by visualizing contrast spots due to pathologic changes was observed by 1H magnetic resonance imaging (MRI). Major metabolites of adult B. malayi observed by 31P-NMR spectroscopy were of sugar phosphates (SP), phosphomonoesters (PME), glycerophosphoryl-ethanolamine (GPE), -choline (GPC), phosphoenolpyruvate (PEP), inorganic phosphate (Pi), nucleoside diphosphosugar and nucleotides-mono, -di and -tri phosphates. PEP and GPC were present in high concentration; PEP being the major energy reservoir and GPC the major phospholipid in this species of filaria. The 31P NMR spectra of testis of mastomys, showed seven major peaks of SP, PME, phosphocreatine (PCr), phosphodiesters (PDE), Pi, and nucleotides di- and tri-phosphates. The 31P-NMR spectra of testis of B. malayi infected animal also consisted of seven major peaks with significant decrease in the SP and PME peak showing changes in the carbohydrate and lipid metabolism of filaria infected testis. Thus, in vivo 31P MRS provided a non-invasive assessment of tissue bioenergetics and phospholipid metabolism.


Asunto(s)
Brugia Malayi/metabolismo , Filariasis/metabolismo , Espectroscopía de Resonancia Magnética , Fosfolípidos/metabolismo , Fosfatos de Azúcar/metabolismo , Enfermedades Testiculares/metabolismo , Testículo/metabolismo , Animales , Brugia Malayi/anatomía & histología , Brugia Malayi/aislamiento & purificación , Femenino , Filariasis/diagnóstico , Imagen por Resonancia Magnética , Masculino , Ratas , Enfermedades Testiculares/diagnóstico , Enfermedades Testiculares/parasitología , Testículo/patología
17.
J Parasitol ; 70(2): 208-12, 1984 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-6470884

RESUMEN

Chronic lymphatic filariasis is accompanied by edema and fibrosis. In order to assess the latter response, the tissue content of collagen was measured in the skin and lymphatic vessels of normal and affected limbs of cats infected by Brugia malayi. Collagen content, expressed per gram wet weight of tissue, was increased in the infected limbs for both kinds of tissues. Moreover, the proportion of acetic acid soluble to total collagen was increased. The degree of crosslinking in soluble collagen was assessed by acrylamide gel electrophoresis and shown to be decreased in infected tissues. These data suggest an increased rate of collagen metabolism in Brugia malayi-infected tissues and provide data for future studies evaluating the efficacy of treatment in chronic experimental filariasis.


Asunto(s)
Colágeno/metabolismo , Filariasis/metabolismo , Sistema Linfático/metabolismo , Piel/metabolismo , Animales , Brugia , Gatos , Colágeno/análisis , Miembro Posterior , Sistema Linfático/análisis , Sustancias Macromoleculares , Piel/análisis , Solubilidad
18.
Folia Parasitol (Praha) ; 30(1): 43-6, 1983.
Artículo en Inglés | MEDLINE | ID: mdl-6341183

RESUMEN

A study was undertaken in cotton rat filarial (L. carinii) model to examine whether the simple goitre is due to increased utilization of iodine by filarial worms. Thyroid function test using radioisotope 131I was taken as the parameter for the study. It was observed that the uptake of 131I by thyroid gland and PB131I in infected group was comparable to control groups. The uptake of 131I by worms was negligible. The thyroid glands of infected group did not reveal any histopathological changes.


Asunto(s)
Filariasis/metabolismo , Yodo/metabolismo , Glándula Tiroides/metabolismo , Animales , Arvicolinae , Filarioidea/metabolismo , Hígado/metabolismo , Masculino
19.
Folia Parasitol (Praha) ; 36(2): 169-75, 1989.
Artículo en Inglés | MEDLINE | ID: mdl-2527791

RESUMEN

The status of glycogen, protein, lipid components, lipid peroxides and a few enzymes of energy metabolism was studied in liver of Mastomys natalensis during the development of Brugia malayi infection. Glycogen and lipid contents were decreased during the patent phase of infection while total protein was slightly altered in latent animals. Phospholipid and triglyceride contents declined at prepatent and patent phase of infection. The levels of lactate and malate dehydrogenases, as well as of adenosine triphosphatases (Na+K+, Mg2+, Ca2+), were significantly elevated and monoamine oxidase activity was decreased at patent phase of infection, while succinic dehydrogenase remained unaltered. The lipid peroxide formation was enhanced in liver during the development of filarial infection.


Asunto(s)
Filariasis Linfática/metabolismo , Filariasis/metabolismo , Hígado/metabolismo , Adenosina Trifosfatasas/análisis , Animales , Brugia , Colesterol/análisis , Metabolismo Energético , Glucógeno/análisis , L-Lactato Deshidrogenasa/análisis , Peróxidos Lipídicos/análisis , Hígado/análisis , Hígado/enzimología , Malato Deshidrogenasa/análisis , Masculino , Monoaminooxidasa/análisis , Muridae , Fosfolípidos/análisis , Proteínas/análisis , Succinato Deshidrogenasa/análisis , Triglicéridos/análisis
20.
Eur J Drug Metab Pharmacokinet ; 11(3): 211-23, 1986.
Artículo en Francés | MEDLINE | ID: mdl-3816877

RESUMEN

The metabolism of diethylcarbamazine (DEC) in healthy and filaria-infected Proechimys oris Rodents was investigated. DEC and 14C labelled DEC were orally administrated (100 mg/kg). The drug was quickly and intensively metabolised. About 90% of the dose administered was eliminated in the urine within 24 hours. Monodeethylation was the major pathway. The major urinary metabolites were ethylcarbamazine and its N-oxide. Traces of N methylpiperazine 2,5 dione and their N-oxide were also found. Elimination was faster in filarial than in healthy animals, but metabolites were the same.


Asunto(s)
Dietilcarbamazina/metabolismo , Infecciones por Dipetalonema/metabolismo , Filariasis/metabolismo , Roedores/metabolismo , Animales , Cromatografía de Gases y Espectrometría de Masas , Masculino , Roedores/parasitología
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