RESUMO
Resistance to quinoline-containing compound has been associated with the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene. We analyzed wild P. falciparum isolates with high levels of chloroquine and mefloquine resistance for their macrorestriction maps of chromosome 5 and sequence of pfmdr1. Two types of chromosome 5 amplification were found. Eleven of 62 resistant isolates displayed Bgl 1 fragments larger than 100 kb. Twenty-nine isolates possessed multiple copies of the fragments. We failed to detect any amplification of this region on chromosome 5 in 22 mefloquine-resistant isolates, suggesting that other mechanisms can mediate the mefloquine-resistant phenotype. There was no direct association between pfmdr1 mutations and chloroquine sensitivity. Resistant lines could have Asn-86 and Tyr-184 or Phe-184, the predicted sequence of those chloroquine-sensitive isolates. No mutation at Asn-1042 and Asp-1246 was detected among these chloroquine-resistant isolates. Therefore, a few base substitutions in the pfmdr1 gene may not be sufficient to account for all chloroquine-resistant phenotypes.
Assuntos
Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Mefloquina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Amodiaquina/farmacologia , Animais , Antimaláricos/uso terapêutico , Cloroquina/farmacologia , Mapeamento Cromossômico , Primers do DNA/química , DNA de Protozoário/química , Eletroforese em Gel de Ágar , Eletroforese em Gel de Campo Pulsado , Humanos , Concentração Inibidora 50 , Mefloquina/uso terapêutico , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Mutação Puntual , Reação em Cadeia da Polimerase , Quinina/farmacologia , Contagem de Cintilação , Análise de Sequência de DNA , TailândiaRESUMO
The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum.
