RESUMEN
Recognizing that enteric tuft cells can signal the presence of nematode parasites, we investigated whether tuft cells are required for the expulsion of the cestode, Hymenolepis diminuta, from the non-permissive mouse host, and in concomitant anti-helminthic responses. BALB/c and C57BL/6 mice infected with H. diminuta expelled the worms by 11 days post-infection (dpi) and displayed DCLK1+ (doublecortin-like kinase 1) tuft cell hyperplasia in the small intestine (not the colon) at 11 dpi. This tuft cell hyperplasia was dependent on IL-4Rα signalling and adaptive immunity, but not the microbiota. Expulsion of H. diminuta was slowed until at least 14 dpi, but not negated, in tuft cell-deficient Pou2f3-/- mice and was accompanied by delayed goblet cell hyperplasia and slowed small bowel transit. Worm antigen and mitogen evoked production of IL-4 and IL-10 by splenocytes from wild-type and Pou2f3-/- mice was not appreciably different, suggesting similar systemic immune reactivity to infection with H. diminuta. Wild-type and Pou2f3-/- mice infected with H. diminuta displayed partial protection against subsequent infection with the nematode Heligmosomoides bakeri. We speculate that, with respect to H. diminuta, enteric tuft cells are important for local immune events driving the rapidity of H. diminuta expulsion but are not critical in initiating or sustaining systemic Th2 responses that provide concomitant immunity against secondary infection with H. bakeri.
Asunto(s)
Himenolepiasis , Hymenolepis diminuta , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Animales , Hymenolepis diminuta/inmunología , Ratones , Himenolepiasis/inmunología , Himenolepiasis/parasitología , Intestino Delgado/inmunología , Intestino Delgado/parasitología , Intestino Delgado/patología , Ratones Noqueados , Femenino , Hiperplasia/inmunología , Hiperplasia/parasitología , Células en PenachoRESUMEN
The tapeworm Hymenolepis diminuta fails to establish in mice. Given the potential for helminth-bacteria interaction in the gut and the influence that commensal bacteria exert on host immunity, we tested if worm expulsion was related to alterations in the gut microbiota. Specific pathogen-free (SPF) mice, treated with broad-spectrum antibiotics, or germ-free wild-type mice were infected with H. diminuta, gut bacterial composition assessed by 16S rRNA gene sequencing, and worm counts, blood eosinophilia, goblet cells, splenic IL-4, -5 and -10, and colonic cytokines/chemokines mRNA were assessed. Effects of a PBS-soluble extract of adult H. diminuta on bacterial growth in vitro was tested. H. diminuta-infected mice displayed increased α and ß diversity in colonic mucosa-associated and fecal bacterial communities, characterized by increased Lachnospiraceae and clostridium cluster XIVa. In vitro analysis revealed that the worm extract promoted the growth of anaerobic bacteria on M2GSC agar. H. diminuta-infection was accompanied by increased Th2 immune responses, and colon from infected mice had increased levels of IL-10, IL-25, Muc2, trefoil factor 3, and ß2-defensin mRNA. SPF-mice treated with antibiotics, or germ-free mice, expelled H. diminuta with kinetics similar to control SPF mice. In both settings, measurements of Th2-immune responses were not significantly different across the groups. Thus, while infection with H. diminuta results in subtle but distinct changes to the colonic microbiota, we have no evidence to support an essential role for gut bacteria in the expulsion of the worm from the mouse host.
Asunto(s)
Colon/microbiología , Microbioma Gastrointestinal , Himenolepiasis/inmunología , Himenolepiasis/microbiología , Himenolepiasis/parasitología , Animales , Antibacterianos/farmacología , Biodiversidad , Citocinas/inmunología , ADN Bacteriano/genética , Heces/microbiología , Interacciones Huésped-Parásitos , Hymenolepis diminuta , Mucosa Intestinal/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , ARN Ribosómico 16S/genética , Organismos Libres de Patógenos EspecíficosRESUMEN
Intestinal helminths induce immune suppressive responses thought to regulate inflammatory diseases including allergies and autoimmune diseases. This study was designed to evaluate whether helminthic infections suppress the natural development of systemic lupus erythematosus (SLE) in NZBWF1 mice. Infection of NZBWF1 SLE-prone mice with two nematodes failed to establish long-lasting settlement. However, the Hymenolepis microstoma (Hm) rodent tapeworm successfully established long-term parasitization of NZBWF1 mice and was used to evaluate the suppressive effects of helminth infection. Ten-month-old NZBWF1 mice developed symptoms including autoantibody generation, proteinuria, glomerular histopathology, and splenomegaly, but mice infected with Hm at 2 months of age did not show any clinical signs. Furthermore, infection with Hm reduced lymphocyte activation and increased regulatory T cells in the spleen and mesenteric lymph nodes. These results indicate that infection with Hm protects NZBWF1 mice from naturally developing SLE and suggest that pathological immunity is attenuated, presumably because of the induction of regulatory T cells.
Asunto(s)
Himenolepiasis/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/prevención & control , Animales , Modelos Animales de Enfermedad , Femenino , Hymenolepis , Terapia de Inmunosupresión/métodos , Activación de Linfocitos , Ratones , Ratones Endogámicos NZB , Organismos Libres de Patógenos Específicos , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Cancer is a high-impact disease throughout the world. A negative correlation has been established between the development of cancer and the Th2 immune response. Infection by helminth parasites is characterized by the induction of a strong and long-lasting Th2 response. The aim of this work was to evaluate the effect of the immune response induced by the infection with the helminth Hymenolepis nana, on the tumorigenesis induced by dimethylbenz-anthracene (DMBA) in mice. METHODOLOGY: Four different groups of 14 female BALB/c mice were formed; Group A, dimethyl sulfoxide (DMSO) (vehicle) was administered cutaneously, Group B infected with H. nana, group C, cutaneously DMBA and finally Group D infected with H. nana and cutaneous DMBA. The tumor load was determined in those animals that developed cancerous lesions. In all groups were determined: serum concentration of IgE, IFNγ, IL-10, IL-5 and malondialdehyde (MDA). The inflammatory infiltrate was analyzed from skin samples and the expression of the main eosinophilic protein and myeloperoxidase was determined. RESULTS: The group previously infected with H. nana had a reduced amount of tumors with smaller size, in comparison to the group that received only DMBA; this reduction was associated with lower levels of IFNγ and IL-10, while levels of IgE, IL-5 and MDA were higher. Further, the number of eosinophils and neutrophils was statistically higher in the animals that were previously infected with the helminth and developed less tumors. CONCLUSION: The immune response induced by H. nana infection is associated with the reduction of tumors probably due to the activity of eosinophils and neutrophils.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/toxicidad , Carcinogénesis/inmunología , Citocinas/inmunología , Himenolepiasis/inmunología , Hymenolepis nana/inmunología , Células Th2/inmunología , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/patología , Femenino , Himenolepiasis/patología , Ratones , Ratones Endogámicos BALB C , Células Th2/patologíaAsunto(s)
Himenolepiasis/inmunología , Hymenolepis diminuta/fisiología , Inmunidad Innata , Enfermedad de Parkinson/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus epidermidis/fisiología , alfa-Sinucleína/inmunología , Animales , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Tolerancia InmunológicaRESUMEN
It has emerged that neutrophils can play important roles in the host response following infection with helminth parasites. Mice infected with the tapeworm, Hymenolepis diminuta, are protected from some inflammatory conditions, accompanied by reduced neutrophil tissue infiltration. Thus, the ability of a phosphate-buffered saline-soluble extract of the worm (H. diminuta extract [HdE]) was tested for (1) its ability to activate murine neutrophils (Ca2+ mobilization, reactive oxygen species (ROS) and cytokine production); and (2) affect neutrophil chemotaxis in vitro to the penta-peptide, WKYMVm, the chemokine, KC, and leukotriene B4. HdE was not cytotoxic to neutrophils, elicited a Ca2+ response and ROS, but not, cytokine (KC, interleukin-10, tumour necrosis factor-α) generation. HdE is not a chemotactic stimulus for murine neutrophils. However, a heat- and trypsin-sensitive, acid-insensitive proteoglycan (sensitive to sodium metaperiodate) in the HdE significantly reduced neutrophil chemotaxis towards WKYMVm or KC, but not LTB4. The latter suggested that the HdE interfered with p38 mitogen-activated protein kinase signalling, which is important in WKYMVm chemotaxis. Corroborating this, immunoblotting revealed reduced phosphorylated p38, and the downstream signal heat-shock protein-27, in protein extracts from HdE + WkYMVm treated cells compared to those exposed to the penta-peptide only. We speculate that HdE can be used to modify the outcome of neutrophilic disease and that purification of the bioactive proteoglycan(s) from the extract could be used as a template to design immunomodulatory drugs targeting neutrophils.
Asunto(s)
Antígenos Helmínticos/metabolismo , Himenolepiasis/inmunología , Hymenolepis diminuta/fisiología , Neutrófilos/inmunología , Proteoglicanos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Antígenos Helmínticos/inmunología , Señalización del Calcio , Extractos Celulares/farmacología , Células Cultivadas , Quimiotaxis , Citocinas/metabolismo , Regulación hacia Abajo , Activación Enzimática , Interacciones Huésped-Parásitos , Masculino , Ratones , Ratones Endogámicos BALB C , Activación Neutrófila , Proteoglicanos/inmunología , Tripsina/metabolismoRESUMEN
In cestodiasis, mechanical and molecular contact between the parasite and the host activates the immune response of the host and may result in inflammatory processes, leading to ulceration and intestinal dysfunctions. The aim of the present study was to identify antigenic proteins of the adult cestode Hymenolepis diminuta by subjecting the total protein extracts from adult tapeworms to 2DE immunoblotting (two-dimensional electrophoresis combined with immunoblotting) using sera collected from experimentally infected rats. A total of 36 protein spots cross-reacting with the rat sera were identified using LC-MS/MS. As a result, 68 proteins, including certain structural muscle proteins (actin, myosin, and paramyosin) and moonlighters (heat shock proteins, kinases, phosphatases, and glycolytic enzymes) were identified; most of these were predicted to possess binding and/or catalytic activity required in various metabolic and cellular processes, and reported here as potential antigens of the adult cestode for the first time. As several of these antigens can also be found at the cell surface, the surface-associated proteins were extracted and subjected to in-solution digestion for LC-MS/MS identification (surfaceomics). As a result, a total of 76 proteins were identified, from which 31 proteins, based on 2DE immunoblotting, were predicted to be immunogenic. These included structural proteins actin, myosin and tubulin as well as certain moonlighting proteins (heat-shock chaperones) while enzymes with diverse catalytic activities were found as the most dominating group of proteins. In conclusion, the present study shed new light into the complexity of the enteric cestodiasis by showing that the H. diminuta somatic proteins exposed to the host possess immunomodulatory functions, and that the immune response of the host could be stimulated by diverse mechanisms, involving also those triggering protein export via yet unknown pathways.
Asunto(s)
Antígenos Helmínticos/inmunología , Himenolepiasis/metabolismo , Hymenolepis diminuta/inmunología , Factores Inmunológicos/metabolismo , Animales , Células Cultivadas , Interacciones Huésped-Parásitos , Humanos , Himenolepiasis/inmunología , Inmunomodulación , Intestino Delgado/inmunología , Estadios del Ciclo de Vida , Masculino , Proteínas de la Membrana , Proteómica , Ratas , Ratas Endogámicas Lew , Úlcera GástricaRESUMEN
The rat tapeworm Hymenolepis diminuta is a parasite of the small intestine of rodents (mainly mice and rats), and accidentally humans. It is classified as a non-invasive tapeworm due to the lack of hooks on the tapeworm's scolex, which could cause mechanical damage to host tissues. However, many studies have shown that metabolites secreted by H. diminuta interfere with the functioning of the host's gastrointestinal tract, causing an increase in salivary secretion, suppression of gastric acid secretion, and an increase in the trypsin activity in the duodenum chyme. Our work presents the biochemical and molecular mechanisms of a parasite-host interaction, including the influence on ion transport and host intestinal microflora, morphology and biochemical parameters of blood, secretion of antioxidant enzymes, expression of Toll-like receptors, mechanisms of immune response, as well as the expression and activity of cyclooxygenases. We emphasize the interrelations between the parasite and the host at the cellular level resulting from the direct impact of the parasite as well as host defense reactions that lead to changes in the host's tissues and organs.
Asunto(s)
Interacciones Huésped-Parásitos , Himenolepiasis/veterinaria , Hymenolepis diminuta/fisiología , Ratas/parasitología , Animales , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/parasitología , Tracto Gastrointestinal/patología , Humanos , Himenolepiasis/sangre , Himenolepiasis/inmunología , Himenolepiasis/patología , Hymenolepis diminuta/inmunología , Inmunidad , Inflamación/sangre , Inflamación/inmunología , Inflamación/patología , Inflamación/veterinaria , Transporte Iónico , Ratas/inmunologíaRESUMEN
Hymenolepis diminuta is a parasitic tapeworm of the rat small intestine and is recognized as a useful model for the analysis of cestode-host interactions. In this study, we analyzed factors affecting the biomass of the tapeworm through use of rat strains carrying genetic mutations, namely X-linked severe combined immunodeficiency (xscid; T, B and NK cells deficiency), nude (rnu; T cell deficiency), and mast cell deficient rats. The worm biomass of F344-xscid rats after infection with 5 cysticercoids was much larger than control F344 rats from 3 to 8â¯weeks. The biomass of F344-rnu rats was also larger than the controls, but was intermediate between F344-xscid and control rats. These observations demonstrated that host immunity can control the maximal tapeworm biomass, i.e., carrying capacity, of the rat small intestine. Both T cell and other immune cells (B and NK cells) have roles in determining the carrying capacity of tapeworms. Total worm biomass and worm numbers in mast cell deficient rats (WsRC-Ws/Ws) were not significantly different from control WsRC-+/+ rats after 3 and 6â¯weeks of primary infection. Mast cell deficient rats displayed reinfection resistance for worm biomass but not worm expulsion. These findings suggest that the mast cell has a role for controlling the biomass of this tapeworm in reinfection alone, but does not affect the rate of worm expulsion. Overall, our findings indicate that the mast cell is not a major effector cell for the control of the carrying capacity of tapeworms. The identity of the major effector cell remains unknown.
Asunto(s)
Interacciones Huésped-Parásitos/inmunología , Himenolepiasis/inmunología , Hymenolepis diminuta/aislamiento & purificación , Intestino Delgado/inmunología , Animales , Biomasa , Himenolepiasis/parasitología , Hymenolepis diminuta/fisiología , Intestino Delgado/parasitología , Mastocitos/inmunología , Ratas , Ratas Endogámicas F344 , Ratas Desnudas , Linfocitos T/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma XRESUMEN
Infection with helminth parasites reduces the severity of concomitant inflammatory disease in adult mice. There is an alarming increase of inflammatory bowel disease (IBD) in children. It is important to determine whether helminth therapy would be of value in pediatric IBD and whether triggering immunological memory to the worm would be anticolitic. Three-week-old (young) and eight-week-old (adult) Balb/c mice were infected with H. diminuta, and infectivity and T helper 2 (Th2) immunity were assessed. Other mice received H. diminuta with or without a crude worm extract ( HdE) 28-42 days postinfection (dpi) with or without dinitrobenzene sulphonic acid [DNBS, 1.5 mg (young) or 3 mg (adults), ir], and colitis was assessed 72 h later. Infected young mice developed Th2 immunity and expelled H. diminuta; expulsion was delayed by ~2 days compared with adult mice. Colitis, as gauged by macroscopic disease and histopathology scores, was less severe in young mice infected 10 days, but not 8 days, before DNBS. Protection against DNBS-induced colitis was accompanied by an increased capacity to make interleukin (IL)-4 and IL-10. Mice infected with H. diminuta were not protected from DNBS-colitis when challenged 28 days later; however, injection of these mice with HdE coincident with DNBS resulted in less disease and increased splenic IL-4 and IL-10. Using a boost (500 µg HdE, 28 dpi) and repeat HdE (100 µg, 42 dpi) regimen with infected mice suppressed DNBS-colitis, as did adoptive transfer of splenic CD4+ T cells from infected mice with low-dose HdE challenge. Should these data translate to IBD, then helminth therapy could be of value in pediatric-onset IBD, and defining the antigen(s) that elicit antihelminth immunological memory could serve as an anticolitic approach in previously infected individuals. NEW & NOTEWORTHY This study demonstrates that juvenile mice are protected from colitis by infection with the tapeworm Hymenolepis diminuta and that using worm antigen to trigger an immunological memory response in previously infected mice can be used to limit the severity of colitis.
Asunto(s)
Antígenos Helmínticos/sangre , Colitis , Himenolepiasis/inmunología , Hymenolepis diminuta/inmunología , Memoria Inmunológica/inmunología , Traslado Adoptivo/métodos , Factores de Edad , Animales , Colitis/inmunología , Colitis/prevención & control , Modelos Animales de Enfermedad , Hymenolepis diminuta/aislamiento & purificación , Interleucina-10/sangre , Interleucina-4/sangre , Ratones , Ratones Endogámicos BALB CRESUMEN
The potential therapeutic value of Moringa oleifera extract (MOE), due to its anti-inflammatory and anti-oxidant effects, has been reported previously. In this study, Hymenolepis nana antigen (HNA) in combination with MOE was used in immunization against H. nana infection. Adult worm and egg counts were taken, while histological changes in the intestine were observed. Mucosal mast (MMCs) and goblet cells (GCs) were stained with specific stains, while serum and intestinal IgA were assayed using enzyme-linked immunosorbent assay (ELISA). Reduced glutathione (GSH) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS) were assayed. Real-time polymerase chain reaction (PCR) was used for detection of mRNA expression in ileum tissue. The results demonstrated an improvement in the architecture of intestinal villi, decreased inducible nitric oxide synthase (iNOs) and TBARS, and increased GSH in HNA, MOE and MOE + HNA groups. In the same groups, an increase in GCs, mucin 2 (MUC2), interleukins (IL)-4, -5 and -9, and stem cell factor (SCF) versus a decrease in both interferon-gamma (IFN-γ) and transforming growth factor (TGF-ß) expression appeared. HNA and MOE + HNA increased serum and intestinal IgA, respectively. MOE decreased MMCs and achieved the highest reductions in both adult worms and eggs. In conclusion, MOE could achieve protection against H. nana infections through decreased TGF-ß, IFN-γ and MMC counts versus increased GC counts, T-helper cell type 2 (Th2) cytokines and IgA level.
Asunto(s)
Himenolepiasis/tratamiento farmacológico , Hymenolepis/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/inmunología , Moringa oleifera/química , Extractos Vegetales/uso terapéutico , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/química , Antihelmínticos/uso terapéutico , Citocinas/efectos de los fármacos , Citocinas/inmunología , Glutatión/análisis , Himenolepiasis/inmunología , Himenolepiasis/parasitología , Inmunoglobulina A/análisis , Inmunoglobulina A/inmunología , Interferón gamma/efectos de los fármacos , Interferón gamma/genética , Interferón gamma/inmunología , Intestinos/parasitología , Peroxidación de Lípido , Ratones , Óxido Nítrico Sintasa/efectos de los fármacos , Óxido Nítrico Sintasa/genética , Recuento de Huevos de Parásitos , Extractos Vegetales/administración & dosificación , Células Th2/efectos de los fármacos , Células Th2/inmunologíaRESUMEN
Infection with parasitic helminths can ameliorate the severity of concomitant inflammatory disease. To use the tapeworm, Hymenolepis diminuta, and to extend this concept by assessing whether triggering a memory response against the worm inhibits dinitrobenzene sulphonic acid (DNBS)-induced colitis in Balb/c mice. Initial studies revealed that oral infection with 1, 3 or 5 H. diminuta cysticercoids 8 days before intrarectal administration of DNBS (3 mg) resulted in less severe inflammation and that infected mice displayed an increased propensity for T helper-2 immunity. A 1 mg dose of a PBS-soluble extract of the worm (HdAg) delivered intraperitoneally concomitant with DNBS was anticolitic as determined by macroscopic and histological disease scores 72 hour post-DNBS. Mice infected 28 days previously had a memory response as determined by HdAg-evoked increases in interleukin (IL)-4 and IL-10 from in vitro stimulated splenocytes and serum anti-H. diminuta IgG. Moreover, mice infected with 5 H. diminuta 28 days previously were protected from DNBS-induced colitis by secondary infection or 100 µg HdAg (ip.) at the time of DNBS treatment. An additional approach to managing inflammatory disease could be infection with H. diminuta followed by eliciting antiworm recall responses.
Asunto(s)
Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/uso terapéutico , Colitis/inmunología , Colitis/prevención & control , Hymenolepis diminuta/inmunología , Memoria Inmunológica/inmunología , Animales , Antígenos Helmínticos/inmunología , Bencenosulfonatos , Colitis/inducido químicamente , Colitis/parasitología , Himenolepiasis/inmunología , Himenolepiasis/parasitología , Interleucina-10/sangre , Interleucina-10/inmunología , Interleucina-4/sangre , Interleucina-4/inmunología , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Hymenolepis nana is the most commonly known intestinal cestode infecting mainly human. This study aimed to investigate the potential effect of chitosan particles (CSP) to enhance the immune system against H. nana infection. Determination of worm burden, egg output, histopathological changes, oxidative stress markers (lipid peroxidation and reduced glutathione), goblet (GCs) and mucosal mast cells (MMCs) counts in intestinal ileum was performed. In addition, levels of intestinal mRNA expression of interleukin (IL)-4, IL-9, stem cell factor (SCF), type I and II interferons (IFN)-α/ γ, tumour necrosis factor (TNF)-α, mucin 2 (MUC2) and inducible nitric oxide synthase (iNOs) were investigated using real-time PCR. The results indicated induced reductions in adult worm and egg counts in infected mice after CSP treatment. This was associated with improvement in tissue morphometric measurements and oxidative stress which were altered after infection. Expression levels of iNOs, IFN-α, IFN-γ, TNF-α and IL-9 were decreased by CSP. Conversely, expression levels of MUC2, IL-4 and SCF increased compared to infected untreated group. In addition, GCs and MMCs counts were normalized by CSP. In conclusion, this study could indicate the immunoprotective effect of CSP against H. nana infection. This was characterized with Th2 anti-inflammatory responses.
Asunto(s)
Quitosano/farmacología , Himenolepiasis/prevención & control , Hymenolepis nana/efectos de los fármacos , Intestinos/efectos de los fármacos , Animales , Quitosano/química , Quitosano/inmunología , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Proteínas del Helminto/genética , Proteínas del Helminto/inmunología , Proteínas del Helminto/metabolismo , Interacciones Huésped-Parásitos/efectos de los fármacos , Interacciones Huésped-Parásitos/inmunología , Humanos , Himenolepiasis/inmunología , Himenolepiasis/parasitología , Hymenolepis nana/inmunología , Hymenolepis nana/fisiología , Interferón-alfa/genética , Interferón-alfa/inmunología , Interferón-alfa/metabolismo , Interferón gamma/genética , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Intestinos/inmunología , Intestinos/parasitología , Ratones , Mucina 2/genética , Mucina 2/inmunología , Mucina 2/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/inmunología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Recuento de Huevos de Parásitos , Tamaño de la Partícula , Sustancias Protectoras/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Interleukin (IL)-22, an immune cell-derived cytokine whose receptor expression is restricted to non-immune cells (e.g. epithelial cells), can be anti-inflammatory and pro-inflammatory. Mice infected with the tapeworm Hymenolepis diminuta are protected from dinitrobenzene sulphonic acid (DNBS)-induced colitis. Here we assessed expulsion of H. diminuta, the concomitant immune response and the outcome of DNBS-induced colitis in wild-type (WT) and IL-22 deficient mice (IL-22-/-) ± infection. Interleukin-22-/- mice had a mildly impaired ability to expel the worm and this correlated with reduced or delayed induction of TH2 immunity as measured by splenic and mesenteric lymph node production of IL-4, IL-5 and IL-13 and intestinal Muc-2 mRNA and goblet cell hyperplasia; in contrast, IL-25 increased in the small intestine of IL-22-/- mice 8 and 12 days post-infection compared to WT mice. In vitro experiments revealed that H. diminuta directly evoked epithelial production of IL-25 that was inhibited by recombinant IL-22. Also, IL-10 and markers of regulatory T cells were increased in IL-22-/- mice that displayed less DNBS (3 mg, ir. 72h)-induced colitis. Wild-type mice infected with H. diminuta were protected from colitis, as were infected IL-22-/- mice and the latter to a degree that they were almost indistinguishable from control, non-DNBS treated mice. Finally, treatment with anti-IL-25 antibodies exaggerated DNBS-induced colitis in IL-22-/- mice and blocked the anti-colitic effect of infection with H. diminuta. Thus, IL-22 is identified as an endogenous brake on helminth-elicited TH2 immunity, reducing the efficacy of expulsion of H. diminuta and limiting the effectiveness of the anti-colitic events mobilized following infection with H. diminuta in a non-permissive host.
Asunto(s)
Colitis/inmunología , Himenolepiasis/inmunología , Hymenolepis diminuta/inmunología , Interleucinas/inmunología , Animales , Interleucina-10/inmunología , Interleucina-4/inmunología , Interleucinas/genética , Ratones Endogámicos BALB C , Ratones Noqueados , Linfocitos T Reguladores/inmunología , Interleucina-22RESUMEN
Neoplasms are more frequent in HIV-positive persons than in non-infected individuals. The incidence of malignancies associated to oncoviruses increases with low CD4 counts in HIV carriers. This is the case for Kaposi sarcoma, Castleman disease or effusive cavity lymphomas due to HHV-8, anorectal or cervical cancer due to human papillomavirus, and Burkitt lymphoma or large B-cell lymphoma due to Epstein-Barr virus.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/parasitología , Transformación Celular Neoplásica/inmunología , Infecciones por VIH/inmunología , Himenolepiasis/inmunología , Hymenolepis nana/crecimiento & desarrollo , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos , Infecciones por VIH/complicaciones , Infecciones por VIH/parasitología , Humanos , Himenolepiasis/complicaciones , Huésped InmunocomprometidoRESUMEN
Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14 d (but not 3 d) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-ß than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-ß and the generation of, or cooperation with, a regulatory macrophage.
Asunto(s)
Linfocitos B/inmunología , Colitis/inmunología , Himenolepiasis/inmunología , Hymenolepis diminuta/inmunología , Macrófagos/inmunología , Animales , Antígenos CD19/biosíntesis , Antígenos CD1d/biosíntesis , Bencenosulfonatos , Antígenos CD40/inmunología , Antígenos CD5/biosíntesis , Colitis/inducido químicamente , Colitis/terapia , Sulfato de Dextran , Proteínas de Homeodominio/genética , Himenolepiasis/parasitología , Inmunomodulación/inmunología , Inmunoterapia , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucina-4/inmunología , Lipopolisacáridos , Masculino , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Oxazolona , Receptores de IgE/biosíntesis , Células TH1/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Toll-like receptors in the gastrointestinal tract can influence intestinal homeostasis and play a role in the repair and restitution of intestinal epithelium following tissue damage. In our previous study a statistically significant increase in the level of TLR4 and TLR2 gene expression was observed in rats in early stages of hymenolepidosis. Moreover, the immunopositive cell number and the intensity of immunohistochemical staining (indicating the presence of TLRs within intestinal epithelial cells) increased over the infection period. In this paper, we determined changes in the expression of TLR2 and TLR4 and the number of anaerobic intestinal commensal bacteria in Hymenolepis diminuta infected rats. In the isolated jejunum of infected rats at 16 days post infection (dpi), the expression of TLR4 and TLR2 was significantly higher than uninfected rats. In the colon, a statistically significantly increased expression of TLR2 was observed from 16 to 40 dpi, and TLR4 from 16 to 60 dpi. The jejunum and colon of infected rats contained Gram-negative bacteria (Escherichia coli), Gram-positive bacteria (Enterococcus, Streptococcus, Staphylococcus, Bacillus, Lactobacillus) and Candida. The total number of intestinal bacteria was higher in H. diminuta infected rats, but the observed microbiota had only minor effects on the expression of TLR2 and TLR4. Toll-like receptors play a role in maintaining epithelial barrier function in response to enteric pathogens and parasites. In our study, the alteration of TLR2 and TLR4 expression in the infected rats indicates the potential role of the innate immune system in the pathomechanism of this infection.
Asunto(s)
Himenolepiasis/inmunología , Hymenolepis diminuta/fisiología , Intestino Grueso/metabolismo , Intestino Delgado/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Animales , Bacterias/crecimiento & desarrollo , Candida/crecimiento & desarrollo , Enterobacteriaceae/crecimiento & desarrollo , Heces/parasitología , Expresión Génica , Himenolepiasis/genética , Himenolepiasis/parasitología , Inmunohistoquímica , Intestino Grueso/microbiología , Intestino Grueso/parasitología , Intestino Delgado/microbiología , Intestino Delgado/parasitología , Masculino , ARN Mensajero/aislamiento & purificación , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , TriboliumRESUMEN
Parasite infection impacts population dynamics through effects on fitness and fecundity of the individual host. In addition to the known roles of environmental factors, host susceptibility to parasites has a genetic basis that has not been well characterized. We previously mapped quantitative trait loci (QTL) for susceptibility to rat tapeworm (Hymenolepis diminuta) infection in Tribolium castaneum using dominant AFLP markers; however, the resistance genes were not identified. Here, we refined the QTL locations and increased the marker density in the QTL regions using new microsatellite markers, sequence-tagged site markers, and single-strand conformational polymorphism markers. Resistance QTL in three linkage groups (LG3, LG6, and LG8) were each mapped to intervals <1.0 cM between two codominant markers. The effects of 21 genes in the three QTL regions were investigated by using quantitative RT-PCR analysis, and transcription profiles were obtained from the resistant TIW1 and the susceptible cSM strains. Based on transcription data, eight genes were selected for RNA interference analysis to investigate their possible roles in H. diminuta resistance, including cytochrome P450 (LOC657454) and Toll-like receptor 13 (TLR13, LOC662131). The transcription of P450 and TLR13 genes in the resistant TIW1 strains was reduced more than ninefold relative to the control. Moreover, the effects of gene knockdown of P450 and TLR13 caused resistant beetles to become susceptible to tapeworm infection, which strongly suggests an important role for each in T. castaneum resistance to H. diminuta infection.
Asunto(s)
Resistencia a la Enfermedad/genética , Genes de Insecto , Himenolepiasis/inmunología , Tribolium/genética , Animales , Mapeo Cromosómico , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Himenolepiasis/genética , Hymenolepis diminuta/patogenicidad , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Repeticiones de Microsatélite , Polimorfismo Conformacional Retorcido-Simple , Sitios de Carácter Cuantitativo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Transcripción Genética , Tribolium/parasitologíaRESUMEN
The aim of the present study was to determine antioxidant defence mechanisms in the rat and Hymenolepis diminuta after long-term infestation. We determined levels of oxidative stress markers, and activity of antioxidant enzymes in the rat small intestine and in particular parts of H. diminuta. Observed changes in antioxidant enzymes activity in H. diminuta and the rat intestine indicate the defence against parasitic infestation and probably allowed parasite to adapt and live in oxidative stress.
Asunto(s)
Antioxidantes/metabolismo , Himenolepiasis/veterinaria , Hymenolepis diminuta , Animales , Biomarcadores , Enfermedad Crónica , Himenolepiasis/inmunología , Hymenolepis diminuta/inmunología , Estrés Oxidativo , RatasRESUMEN
While parasites and immunity are widely believed to play important roles in the evolution of male ornaments, their potential influence on systems where male weaponry is the object of sexual selection is poorly understood. We experimentally infect larval broad-horned flour beetles with a tapeworm and study the consequent effects on: 1) adult male morphology 2) male-male contests for mating opportunities, and 3) induction of the innate immune system. We find that infection significantly reduces adult male size in ways that are expected to reduce mating opportunities in nature. The sum of our morphological, competition, and immunological data indicate that during a life history stage where no new resources are acquired, males allocate their finite resources in a way that increases future mating potential.