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Background   Plasmodium vivax  is the most prevalent cause of human malaria in tropical regions outside the African continent. The lack of a routine continuous  in vitro  culture of this parasite makes it difficult to develop specific drugs for this disease. To facilitate the development of anti- P. vivax  drugs, bacterial and yeast surrogate models expressing the validated  P. vivax  target dihydrofolate reductase-thymidylate synthase (DHFR-TS) have been generated; however, they can only be used as primary screening models because of significant differences in enzyme expression level and  in vivo  drug metabolism between the surrogate models and  P. vivax  parasites.    Methods   Plasmodium falciparum  and  Plasmodium berghei  parasites were transfected with DNA constructs bearing  P. vivax dhfr-ts  pyrimethamine sensitive (wild-type) and pyrimethamine resistant (mutant) alleles. Double crossover homologous recombination was used to replace the endogenous  dhfr-ts  of  P. falciparum  and  P. berghei  parasites with  P. vivax  homologous genes. The integration of  Pvdhfr-ts  genes via allelic replacement was verified by Southern analysis and the transgenic parasites lines validated as models by standard drug screening assays.    Results  Transgenic  P. falciparum  and  P. berghei  lines stably expressing  Pv DHFR-TS replacing the endogenous parasite DHFR-TS were obtained. Anti-malarial drug screening assays showed that transgenic parasites expressing wild-type  Pv DHFR-TS were pyrimethamine-sensitive, whereas transgenic parasites expressing mutant  Pv DHFR-TS were pyrimethamine-resistant. The growth and sensitivity to other types of anti-malarial drugs in the transgenic parasites were otherwise indistinguishable from the parental parasites.    Conclusion  With the permanent integration of  Pvdhfr-ts  gene in the genome, the transgenic  Plasmodium  lines expressing  Pv DHFR-TS are genetically stable and will be useful for screening anti- P. vivax  compounds targeting  Pv DHFR-TS. A similar approach could be used to generate transgenic models specific for other targets of interest, thus facilitating the development of anti- P. vivax  drugs in general.

malaria journal

Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening