Upregulation of gametocytogenesis in anti-malarial drug-resistant Plasmodium falciparum

Abstract

The deadliest form of human malaria is primarily caused by the protozoan parasite Plasmodium falciparum. These parasites establish pathogenicity in the human host with a very low number of sexual forms or gametocytes, which are transmitted to the mosquitoes. Several studies have reported that exposing artemisinin-sensitive P. falciparum rings to a low concentration of dihydroartemisinin (DHA) results in dormancy, and the artemisinin-induced dormant (AID) forms are recovered into normal growth stages after 5-20days. In this study, artemisinin-resistant P. falciparum parasites were tested for the development of AID forms and their recovery. Interestingly, it was found that exposure of an asynchronous culture of artemisinin-resistant P. falciparum IPC 5202 to DHA, a line carrying a mutation in the PfK13 gene that is linked to artemisinin resistance, also results in dormancy. Both the ring and some late stages of these AID forms recovered after 10-15days. Furthermore, a high proportion of the recovered dormant forms developed into sexual forms or gametocytes after 3-4weeks, which is almost a 7-8 times higher rate of conversion of asexual to sexual forms (gametocytes) or the malaria transmissible forms. In contrast, only early ring forms of artemisinin-sensitive parasites recovered slowly, and additional exposure of these parasites to artemisinin resulted in complete clearance within a week. This is in contrast to the resistant parasites exposed to a second dose of artemisinin, which resulted in a very high rate of dormancy and recovery into sexual forms or gametocytes.