Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Infect Genet Evol ; 28: 635-47, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24929123

RESUMEN

Novel strategies to directly thwart malaria transmission are needed to maintain the gains achieved by current control measures. Transmission-blocking interventions (TBIs), namely vaccines and drugs targeting parasite or mosquito molecules required for vector-stage parasite development, have been recognized as promising approaches for preventing malaria transmission. However, the number of TBI targets is limited and their degree of conservation among the major vector-parasite systems causing human disease is unclear. Therefore, discovery and characterization of novel proteins involved in vector-stage parasite development of Plasmodium falciparum and Plasmodium vivax is paramount. We mined the recent Anopheles gambiae midgut lipid raft proteome for putative mosquito-derived TBI targets and characterized a secreted glycoconjugate of unknown function, AgSGU. We analyzed molecular variation in this protein among a range of anopheline mosquitoes, determined its transcriptomic and proteomic profiles, and conducted both standard and direct membrane feeding assays with P. falciparum (lab/field) and P. vivax (field) in An. gambiae and Anopheles dirus. We observed that α-AgSGU antibodies significantly reduced midgut infection intensity for both lab and field isolates of P. falciparum in An. gambiae and An. dirus. However, no transmission-reducing effects were noted when comparable concentrations of antibodies were included in P. vivax-infected blood meals. Although antibodies against AgSGU exhibit transmission-reducing activity, the high antibody titer required for achieving 80% reduction in oocyst intensity precludes its consideration as a malaria mosquito-based TBI candidate. However, our results suggest that P. falciparum and P. vivax ookinetes use a different repertoire of midgut surface glycoproteins for invasion and that α-AgSGU antibodies, as well as antibodies to other mosquito-midgut microvillar surface proteins, may prove useful as tools for interrogating Plasmodium-mosquito interactions.


Asunto(s)
Anopheles/metabolismo , Anopheles/parasitología , Proteínas de Insectos/metabolismo , Malaria Falciparum/transmisión , Malaria Vivax/transmisión , Plasmodium falciparum/patogenicidad , Plasmodium vivax/patogenicidad , Secuencia de Aminoácidos , Animales , Anopheles/genética , Evolución Molecular , Tracto Gastrointestinal/metabolismo , Expresión Génica , Variación Genética , Proteínas de Insectos/química , Proteínas de Insectos/genética , Datos de Secuencia Molecular , Selección Genética , Alineación de Secuencia
2.
Infect Immun ; 82(2): 818-29, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24478095

RESUMEN

Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.


Asunto(s)
Anopheles/parasitología , Transmisión de Enfermedad Infecciosa/prevención & control , Proteínas de Insectos/inmunología , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Malaria Vivax/prevención & control , Animales , Femenino , Proteínas de Insectos/administración & dosificación , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/transmisión , Malaria Vivax/transmisión , Masculino , Ratones , Ratones Endogámicos BALB C
3.
Bioorg Med Chem ; 21(17): 5275-81, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23859775

RESUMEN

We have synthesized poly-γ-glutamic acid (PGA) modified with a synthetic trivalent glyco-ligand (TriGalNAc) for the hepatocyte asialoglycoprotein receptor (ASGP-R). We investigated in vivo distribution of unmodified PGA and TriGalNAc-modified PGA (TriGalNAc-PGA) in mice after intravenous injection. Most of unmodified PGA administered was transported to the bladder over 20-80min, suggesting a rapid excretion of unmodified PGA into urine. In contrast, TriGalNAc-PGA was found exclusively in the liver over the same period of time. We further synthesized TriGalNAc-PGA-primaquine conjugate (TriGalNAc-PGA-PQ), and investigated binding, uptake, and catabolism of the conjugate by rat hepatocytes. Our studies indicated that approximately 250ng per million cells of the conjugate bound to one million rat hepatocytes at 0°C, and approximately 2µg per million cells of the conjugate was taken up over 7h incubation at 37°C. Furthermore, our results suggested that TriGalNAc-PGA-PQ was almost completely degraded over 24h, and small degradation products were secreted into cell culture medium. The results described in this report suggest that the TriGalNAc ligand can serve as an excellent targeting device for delivery of PGA-conjugates to the liver hepatocytes, and rat hepatocytes possess sufficient capacity to digest PGA even modified with other substituents.


Asunto(s)
Hepatocitos/metabolismo , Ácido Poliglutámico/metabolismo , Primaquina/química , Animales , Células Cultivadas , Femenino , Ratones , Microscopía Fluorescente , Ácido Poliglutámico/química , Ratas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA