The contribution of Plasmodium falciparum genetic diversity to differentiate drug response in gametocytes

Abstract

Late-stage gametocytes of P. falciparum parasites are responsible for the ongoing human-to-mosquito transmission of malaria disease. To block transmission, novel gametocytocidal compounds are required. It is thus important to determine ex vivo efficacy against diverse, contemporary clinical isolates as an early filter to provide confirmation of novel gametocytocidal activity in the field. This study hypothesizes that differences in drug responses in late-stage gametocytes of clinical isolates can be correlated with the extent of genetic diversity of clinical isolates. Previously, potent phosphatidylinositol 4-kinase (PI4K) inhibitors indicated differential drug response, which was observed in transmissible stages of ex vivo southern African P. falciparum clinical isolates. These differential drug responses were not only limited to kinase inhibitors, but also seen with endoperoxide and ATP4 inhibitors that were used in the current study. Microsatellite (MS) and single nucleotide polymorphism (SNP) markers determined the allelic variation of clinical isolates, and therefore genetic complexity can clarify differential drug response in isolates. Here we confirm that isolates from the high transmission areas are characterised by a high multiplicity of infection (MOI) and isolates exhibit many unique alleles. This study also shows that there is a relationship between gametocyte production and isolates that are genetically diverse. Furthermore, the study presents SNP barcoding as a more sensitive and robust genotyping technique, as it was able to correlate differential drug response to genetic complexity of clinical isolates.