RESUMEN
Schistosome worms inhabit mammalian mesenteric veins. Their eggs cause chronic inflammation, which progresses to periportal fibrosis in 5 to 30% of cases, increasing portal blood pressure and leading to esophageal varices. Episodes of bleeding cause hepatic necrosis and may ultimately lead to hepatic failure and the death of the patient. Schistosome infections can also cause pulmonary hypertension and heart failure. The mechanisms of fibrogenesis and fibrolysis are beginning to be unraveled, but it remains unclear why disease occurs only in certain subjects, as also observed for other types of chronic liver inflammation, as in hepatitis C or B. We summarize here the results that showed that fibrosis progression is determined by a genetic locus on chromosome 6. The CCN2 gene at this locus, encodes CTGF that is a crucial regulator of fibrosis. Two groups of CCN2 polymorphisms independently modulate the progression of hepatic fibrosis. These results were obtained in an Asian population, but were extended to humans living in Africa and South America and are presently tested in liver fibrosis of other etiological origins.
Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/fisiología , Predisposición Genética a la Enfermedad , Cirrosis Hepática/genética , Parasitosis Hepáticas/genética , Esquistosomiasis/genética , Enfermedades del Bazo/genética , Animales , Pueblo Asiatico/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Progresión de la Enfermedad , Estudios de Asociación Genética , Humanos , Cirrosis Hepática/etnología , Cirrosis Hepática/etiología , Cirrosis Hepática/parasitología , Parasitosis Hepáticas/etnología , Parasitosis Hepáticas/etiología , Schistosoma/fisiología , Esquistosomiasis/complicaciones , Esquistosomiasis/etnología , Índice de Severidad de la Enfermedad , Enfermedades del Bazo/etnología , Enfermedades del Bazo/etiología , Enfermedades del Bazo/parasitologíaAsunto(s)
Anticuerpos Antiprotozoarios/análisis , Antígenos de Protozoos , Leishmaniasis Cutánea/diagnóstico , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Leishmania braziliensis/inmunología , Reacción en Cadena de la Polimerasa , América del SurRESUMEN
Parasites cause much suffering mainly in countries of the southern hemisphere. Hundreds of millions of individuals are infected by schistosomes, leishmanias, plasmodiums, trypanosomes, and various other parasites, and severe clinical disease occurs in a sizable fraction of the infected population causing death and severe sequelae. The outcome, asymptomatic, subclinical or clinical disease, of an infection depends mostly on the parasite and on its host. Several groups analyzing the genetics of human susceptibility to parasites have began to identify the critical steps of the pathogenic mechanisms in a few parasitic infections such as malaria and schistosomiasis. The present article, which is not meant to be an exhaustive review of the field, illustrates the progresses made in this field from pioneer studies in animals to works in endemic populations using modern strategies of human genetics.
Asunto(s)
Enfermedades Parasitarias/genética , Mapeo Cromosómico , Eritrocitos/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Parasitarias/parasitologíaRESUMEN
A previous study performed in adolescents living in an area endemic for Schistosoma mansoni in Brazil has shown that a 37 kDa schistosome surface antigen is a selective target for antibodies in sera from those who were resistant to reinfection. This antigen was shown by molecular cloning to be the schistosome GAPDH. The aim of the present work was to assess whether peptides corresponding to GAPDH antigenic determinants could be used in a subunit vaccine. Five B cell and two T cell epitopic regions were identified on Sm37-GAPDH. One of the B cell determinants (Sm37-5, aa 268-289) is highly antigenic in human infections and antibody reactivity toward this determinant is associated with resistance to reinfection. Mice and rats immunized with Sm37-5 were partially protected against a challenge infection, indicating that this peptide can induce protective immunity. Analysis of Sm37-5 amino acid sequence indicated that this antigenic determinant is likely conserved among other pathogenic strains of schistosome (S. haematobium, S. intercalatum and S. japonicum), although it shows major amino acid differences with the corresponding human GAPDH sequence. All together these results indicate that Sm37-5 should be considered as a candidate component for an anti-schistosome subunit vaccine.
Asunto(s)
Antígenos Helmínticos/genética , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Gliceraldehído-3-Fosfato Deshidrogenasas/inmunología , Schistosoma mansoni/genética , Schistosoma mansoni/inmunología , Vacunas Sintéticas/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Antígenos Helmínticos/química , Linfocitos B/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Gliceraldehído-3-Fosfato Deshidrogenasas/química , Humanos , Epítopos Inmunodominantes/química , Epítopos Inmunodominantes/genética , Ratones , Ratones Endogámicos CBA , Persona de Mediana Edad , Modelos Moleculares , Datos de Secuencia Molecular , Peso Molecular , Conformación Proteica , Ratas , Ratas Endogámicas Lew , Schistosoma/enzimología , Schistosoma/genética , Schistosoma/inmunología , Schistosoma mansoni/enzimología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/prevención & control , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Linfocitos T/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
Studies of anti-S. mansoni immunological responses in individuals living in endemic areas identified immunogens (Sm37-GAPDH and Sm10-DLC) with vaccine candidate properties. Analysis of the epitopes of these immunogens indicated that: (i) Sm37-5 is a major B-cell epitope of Sm37-GAPDH and the IgG antibody reactivity toward this determinant is associated with resistance to reinfection; (ii) Sm10-T is a T-cell epitope of the major T-cell immunogen Sm10-DLC. This led us to test a multiple antigen peptide (MAP) containing Sm37-5 and Sm10-T as an anti-schistosome vaccine. This MAP induced a significant protective immune response in mice when injected in Freund's adjuvant or coadsorbed with GM-CSF on aluminium hydroxide. In the latter case the physical link between the cytokine and the antigen via the coadsorption on alum was necessary to obtain a protective response. Results of the antibody response indicated that when the MAP and GM-CSF were coadsorbed on alum, the antibody response against the Sm10-T epitope located in the NH(2)-terminal position was significantly amplified up to 30% of the anti-Sm37-5 response.
Asunto(s)
Antígenos Helmínticos/administración & dosificación , Schistosoma mansoni/inmunología , Vacunas Sintéticas/administración & dosificación , Compuestos de Alumbre , Secuencia de Aminoácidos , Animales , Antígenos Helmínticos/genética , Linfocitos B/inmunología , Dineínas/genética , Dineínas/inmunología , Epítopos/administración & dosificación , Epítopos/genética , Femenino , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Gliceraldehído-3-Fosfato Deshidrogenasas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Técnicas de Inmunoadsorción , Ratones , Ratones Endogámicos CBA , Datos de Secuencia Molecular , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Schistosoma mansoni/enzimología , Schistosoma mansoni/genética , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/prevención & control , Linfocitos T/inmunología , Vacunas Sintéticas/genéticaRESUMEN
Human susceptibility to Schistosoma mansoni infections is controlled by the SM1 locus on chromosome 5 in q31-q33. This genetic region encodes cytokines which regulate the development of helper T lymphocytes. In the present work, a clonal analysis of CD4(+) T lymphocytes of homozygous resistant and homozygous susceptible subjects was undertaken to evaluate whether SM1 controls helper T-cell differentiation. Of 121 CD4(+) T-cell clones (TCC) from three susceptible (S) and three resistant (R) subjects, 68 proliferated when stimulated by parasite antigens. Parasite-specific TCC derived from susceptible subjects (33 STCC) produced 10- to 1,000-fold less interleukin-4 and -5 than TCC from resistant subjects (25 RTCC). Clones from both patient groups produced, however, the same amount of gamma interferon. Parasite-specific STCC were type 1 helper (Th1) or Th0/1, whereas RTCC were either Th2 or Th0/2. These results, together with the localization of SM1 in 5q31-q33, indicate that the SM1 locus controls the differentiation of Th2 lymphocytes.
Asunto(s)
Cromosomas Humanos Par 5 , Esquistosomiasis mansoni/genética , Células Th2/inmunología , Adolescente , Adulto , Animales , Diferenciación Celular , Niño , Predisposición Genética a la Enfermedad/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inmunofenotipificación , Interleucina-4/biosíntesis , Interleucina-5/biosíntesis , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunologíaRESUMEN
BACKGROUND/AIMS: The tropical parasite Schistosoma mansoni causes granulomatous inflammation following lodging of eggs in portal capillaries. In vitro studies indicated that the host reaction should involve reactive oxygen intermediates; however, it is not known what occurs in vivo at the site of the disease. Moreover, the ultimate pathophysiological effects of oxidative processes depend upon antioxidant factors, which are investigated in this study. METHODS: We explored the changes in the major enzyme activities involved in liver redox metabolism during the course of infection and, for some of them, the mRNA expression. We also measured the reduced glutathione and lipid peroxide levels in the liver. RESULTS: We found that the deposition of parasite eggs triggers the release of endogenous eosinophil peroxidase; enzyme activity developed in the immediate vicinity of the eggs and it increased dramatically with time. However, Cu,Zn-superoxide dismutase, catalase and glutathione peroxidase activities decreased drastically. In contrast, glutathione transferase was unaffected. There was no proportional decrease in mRNA levels for the H2O2 scavenging enzymes. Reduced glutathione concentrations also dropped as a result of infection. Lastly, a two-fold increase in the levels of hepatic products generated by lipid peroxidation was observed. CONCLUSIONS: These results show that on the one hand oxidative processes occurred at the site of granulomatous inflammation and on the other hand the antioxidant capacity of the liver decreased, leading to the generation of lipid peroxides. The resulting imbalance between pro- and anti-oxidant processes may play a central role in the pathology associated with schistosomiasis.
Asunto(s)
Antioxidantes/metabolismo , Catalasa/metabolismo , Eosinófilos/enzimología , Glutatión Peroxidasa/metabolismo , Hígado/metabolismo , Esquistosomiasis mansoni/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Catalasa/genética , Femenino , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Glutatión Transferasa/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos CBA , Óvulo/citología , Oxidación-Reducción , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esquistosomiasis mansoni/sangre , Esquistosomiasis mansoni/patología , Superóxido Dismutasa/genética , Transcripción GenéticaRESUMEN
A previous study has shown that Sm37-5 is a major B cell epitope of Sm37-GAPDH. This epitope is highly antigenic in human infections and IgG antibody reactivity toward this determinant is associated with adolescent resistance to reinfection. This led us to test a synthetic peptide corresponding to Sm37-5, coupled to ovalbumin, as an anti-schistosome vaccine. Although mice injected with Sm37-5-OVA in Freund's adjuvant showed significant protection, immunization in aluminium hydroxide failed to induce protection. The adjuvant effect of cytokines (GM-CSF or IL-12) associated with the antigen on alum was investigated. With each of these two cytokines, significant reductions in the worm burden were obtained (32-38% with GM-CSF and 27% with IL-12, respectively). In addition, a reduction of the egg number trapped in the liver of immunized mice was also observed. Thus, protections were obtained with formulations that could potentially be used in humans.
Asunto(s)
Compuestos de Alumbre , Epítopos de Linfocito B/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Interleucina-12/inmunología , Ovalbúmina/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adsorción , Animales , Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/administración & dosificación , Antígenos Helmínticos/inmunología , Femenino , Gliceraldehído-3-Fosfato Deshidrogenasas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Inmunidad Innata/inmunología , Inmunoglobulina G/biosíntesis , Inyecciones Intramusculares , Interleucina-12/administración & dosificación , Ratones , Ratones Endogámicos CBA , Peso Molecular , Ovalbúmina/administración & dosificación , Esquistosomiasis mansoni/prevención & controlRESUMEN
A study of GB-C virus/Hepatitis G virus (GBV-C/ HGV) infection was carried out in a rural population of Northeastern Brazil, in which the prevalence of schistosomiasis is 80-90%. Despite the absence of parenteral risk exposure, the prevalence of GBV-C/HGV markers of infection was found to be unusually increased: viremia, 16.4%; specific antibody, 18.3%. It is therefore suspected that helminth infection influenced the immune response to GBV-C/HGV infection by shifting the balance of cytokine responses from Th1 to Th2, resulting in a delayed viral clearance. Phylogenetic analysis of viral isolates did not provide evidence for high rates of sexual or mother-to-infant viral transmission. The study revealed that viral strains belonged to types 1 and 2 only (predominant in Africa and Europe, respectively), suggesting that GBV-C/HGV was introduced into the New World by white conquerors and black slaves since the 16th century.
Asunto(s)
Flaviviridae , Hepatitis Viral Humana/epidemiología , Esquistosomiasis/complicaciones , Regiones no Traducidas 5'/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Niño , ADN Viral/análisis , Salud de la Familia , Femenino , Flaviviridae/clasificación , Flaviviridae/genética , Flaviviridae/inmunología , Anticuerpos Antihepatitis/sangre , Hepatitis Viral Humana/complicaciones , Hepatitis Viral Humana/transmisión , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Prevalencia , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esquistosomiasis/epidemiologíaRESUMEN
Three hundred million individuals are at risk of infection by schistosomes and around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Previously, we reported evidence, based on a segregation analysis in Brazilian pedigrees, that intensity of infection by Schistosoma mansoni was influenced by a major gene, indicating that host genetic factors are probably critical in controlling schistosome infection and disease development. To localize this gene, referred to as SM1, we performed a genome-wide study on 142 Brazilian subjects belonging to 11 informative families Our results show a linkage to only one region, on chromosome 5q31-q33, with maximum two-point lod scores of +4.74 and +4.52 for D5S636 and the colony stimulating factor-1 receptor marker (CSF1R), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. This region contains several candidate genes encoding immunological molecules that were shown to play important roles in human protection against schistosomes.
Asunto(s)
Cromosomas Humanos Par 5/genética , Ligamiento Genético , Esquistosomiasis mansoni/genética , Brasil , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Receptor de Factor Estimulante de Colonias de Macrófagos/genéticaRESUMEN
Vaccine-induced immunity to Schistosoma mansoni infection depends on the specific priming of certain T cell subsets and on the recall of this response by natural infections months or years after vaccine administration. Thus, those schistosome proteins that activate T cells in individuals stimulated by natural infections are potential candidate vaccine antigens. In the present study, we identified and purified one such T cell-stimulating antigen and evaluated its immunological properties in subjects living in an area endemic for Schistosoma mansoni. Chromatography fractions (gel filtration, followed by ion exchange chromatography) of soluble extracts of schistosomula were screened for their ability to stimulate schistosome-specific T cell clones derived from a subject sensitized by natural infection. A fraction stimulating most clones was identified and characterized. A few nanograms of this fraction, containing a major 9-10-kDa component, stimulated the T helper cells of most adults living in an endemic area of Brazil, and was able to trigger a strong cutaneous immediate hypersensitivity reaction. In contrast, children reacted weakly to this antigen preparation both in blastogenesis and in skin tests, although they mounted a significant reaction to crude larval antigen preparations. In conclusion, this work identifies a schistosomula antigen that induces a strong T cell response in adults sensitized by natural infections. This T cell response develops gradually in children and adolescents, is apparently not restricted by the HLA haplotypes common in the study area, and allows the production of parasite-specific IgE antibodies. Thus, this T cell response has some features of the immune response that is believed to protect chronically exposed humans from reinfection.
Asunto(s)
Antígenos Helmínticos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Linfocitos T/inmunología , Adulto , Animales , Formación de Anticuerpos , Antígenos Helmínticos/aislamiento & purificación , Brasil/epidemiología , División Celular/inmunología , Células Clonales , Humanos , Inmunofenotipificación , Masculino , Esquistosomiasis mansoni/epidemiología , Esquistosomiasis mansoni/prevención & controlRESUMEN
The design of programs for the control of endemies requires the knowledge of the principal factors that determine parasite transmission and infection levels in exposed populations. In the studies summarized in this article, the role of environmental and host specific factors in the infection by S. mansoni have been evaluated. It is shown that a limited number of factors actually influences infection intensity: water contacts, age, and sex were shown to account for 20 to 25% of infection variance, while 35 to 40% of it was accounted for by the effect of a major codominant gene. A remarkable fact is the important weighting (around 55% of the variance) of factors (the major gene and age) that influence human capacities of resistance. This observation strongly supports control measures aimed at increasing human resistance, such as vaccination. The effect of age on the development of resistance has now been observed in several studies on S. mansoni or S. haematobium. It is, therefore, a constant finding in schistosomiasis infections that resistance develops extremely slowly requiring a long period of exposure to the parasite and repeated infections. These studies provide strong incentives to increase efforts in the evaluation of the immune response of subjects living in endemic areas. Such evaluations are necessary to define vaccine and vaccination programs, and they are also urgently needed to evaluate the effects of chemotherapy on the development of immunity in children and adolescents, as well as on the persistence of protective immunity in adults. Immunological studies begin to provide a clearer picture of the role of acquired immunity in human protection against S. mansoni. It is increasingly clear that the slow development of resistance in children, as well as its alteration in certain age groups, are related to the maturation of parasite specific immunity and its alteration by specific immune factors. Thus, the development of resistance is associated with the maturation of IgE-dependent immunity, whereas blocking Ab may interfere in children and adolescents with the expression of full resistance. This finding raises the question as to whether a vaccine could include major allergens without triggering the well-known deleterious side effects associated with hypersensitivity reactions. The absence of such reactions in subjects with high parasite-specific IgE levels who are exposed to daily infections suggests that this may be feasible.