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1.
Nature ; 582(7810): 104-108, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32427965

RESUMEN

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.


Asunto(s)
Apoptosis/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Parásitos/inmunología , Plasmodium falciparum/citología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Adolescente , Adulto , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/química , Antígenos de Protozoos/inmunología , Aotidae/inmunología , Aotidae/parasitología , Caspasas/metabolismo , Niño , Estudios de Cohortes , ADN Protozoario/química , ADN Protozoario/metabolismo , Activación Enzimática , Eritrocitos/parasitología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Kenia , Vacunas contra la Malaria/inmunología , Malaria Falciparum/parasitología , Masculino , Ratones , Parásitos/citología , Parásitos/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrollo , Proteínas Protozoarias/química , Tanzanía , Trofozoítos/citología , Trofozoítos/crecimiento & desarrollo , Trofozoítos/inmunología , Vacuolas/inmunología
2.
Sci Rep ; 8(1): 17871, 2018 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-30552383

RESUMEN

Major complications and mortality from Plasmodium falciparum malaria are associated with cytoadhesion of parasite-infected erythrocytes (IE). The main parasite ligands for cytoadhesion are members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Interactions of different host receptor-ligand pairs may lead to various pathological outcomes, like placental or cerebral malaria. It has been shown previously that IE can bind integrin αVß3. Using bead-immobilized PfEMP1 constructs, we have identified that the PFL2665c DBLδ1_D4 domain binds to αVß3 and αVß6. A parasite line expressing PFL2665c binds to surface-immobilized αVß3 and αVß6; both are RGD motif-binding integrins. Interactions can be inhibited by cyloRGDFV peptide, an antagonist of RGD-binding integrins. This is a first, to the best of our knowledge, implication of a specific PfEMP1 domain for binding to integrins. These host receptors have important physiological functions in endothelial and immune cells; therefore, these results will contribute to future studies and a better understanding, at the molecular level, of the physiological outcome of interactions between IE and integrin receptors on the surface of host cells.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Adhesión Celular , Eritrocitos/fisiología , Eritrocitos/parasitología , Integrina alfaVbeta3/metabolismo , Integrinas/metabolismo , Plasmodium falciparum/crecimiento & desarrollo , Proteínas Protozoarias/metabolismo , Humanos , Unión Proteica
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