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1.
Infect Immun ; 85(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28760933

RESUMO

Plasmodium falciparum, the parasite that causes the deadliest form of malaria, has evolved multiple proteins known as invasion ligands that bind to specific erythrocyte receptors to facilitate invasion of human erythrocytes. The EBA-175/glycophorin A (GPA) and Rh5/basigin ligand-receptor interactions, referred to as invasion pathways, have been the subject of intense study. In this study, we focused on the less-characterized sialic acid-containing receptors glycophorin B (GPB) and glycophorin C (GPC). Through bioinformatic analysis, we identified extensive variation in glycophorin B (GYPB) transcript levels in individuals from Benin, suggesting selection from malaria pressure. To elucidate the importance of the GPB and GPC receptors relative to the well-described EBA-175/GPA invasion pathway, we used an ex vivo erythrocyte culture system to decrease expression of GPA, GPB, or GPC via lentiviral short hairpin RNA transduction of erythroid progenitor cells, with global surface proteomic profiling. We assessed the efficiency of parasite invasion into knockdown cells using a panel of wild-type P. falciparum laboratory strains and invasion ligand knockout lines, as well as P. falciparum Senegalese clinical isolates and a short-term-culture-adapted strain. For this, we optimized an invasion assay suitable for use with small numbers of erythrocytes. We found that all laboratory strains and the majority of field strains tested were dependent on GPB expression level for invasion. The collective data suggest that the GPA and GPB receptors are of greater importance than the GPC receptor, supporting a hierarchy of erythrocyte receptor usage in P. falciparum.


Assuntos
Eritrócitos/fisiologia , Eritrócitos/parasitologia , Glicoforinas/genética , Plasmodium falciparum/patogenicidade , Biologia Computacional , Glicoforinas/metabolismo , Humanos , Ligantes , Plasmodium falciparum/imunologia , Plasmodium falciparum/fisiologia , Ligação Proteica , Proteômica , Receptores de Superfície Celular/metabolismo
2.
Science ; 348(6235): 711-4, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25954012

RESUMO

Efforts to identify host determinants for malaria have been hindered by the absence of a nucleus in erythrocytes, which precludes genetic manipulation in the cell in which the parasite replicates. We used cultured red blood cells derived from hematopoietic stem cells to carry out a forward genetic screen for Plasmodium falciparum host determinants. We found that CD55 is an essential host factor for P. falciparum invasion. CD55-null erythrocytes were refractory to invasion by all isolates of P. falciparum because parasites failed to attach properly to the erythrocyte surface. Thus, CD55 is an attractive target for the development of malaria therapeutics. Hematopoietic stem cell-based forward genetic screens may be valuable for the identification of additional host determinants of malaria pathogenesis.


Assuntos
Antígenos CD55/genética , Eritrócitos/parasitologia , Interações Hospedeiro-Parasita/genética , Malária Falciparum/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/patogenicidade , Animais , Diferenciação Celular/genética , Células Cultivadas , Eritrócitos/citologia , Eritrócitos/metabolismo , Testes Genéticos , Células-Tronco Hematopoéticas/citologia , Humanos , Receptores de Hialuronatos/genética , RNA Interferente Pequeno/genética
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