Background: Investigation of human-mosquito transmission of artemisinin-resistant parasites is a priority to contain the spread of drug resistance. An artemisinin-resistance induced blood stage malaria (IBSM) model has been established, where subjects are infected with a P. falciparum artemisinin-resistant strain “K13” (R539T). The present study aimed to describe the dynamics of gametocytemia and the effect of atovaquone/proguanil (A/P) on transmission to Anopheles stephensi mosquitoes
Methods: This work is an exploratory component of a randomised trial (ACTRN12617001394336) where subjects were inoculated with either ~2,800 of K13 (n=7) or 3D7 (artemisinin sensitive; n=3) parasites and received a single-dose of artesunate (2 mg/kg) on day 9 post-inoculation. First recrudescent infections were treated with piperaquine and second recrudescence with A/P. Expression of female (pfs25) and male (pfMGET) gametocyte markers were measured from day 9 onwards by qRT-PCR. The 6 subjects with the highest level of pfs25 transcripts were selected to investigate transmission by performing direct feeding assay (DFA) and membrane feeding assay (MFA) on day 23 post-inoculation. Gametocytes were enriched by Percoll gradient prior to MFA. Midguts were dissected 8 days later, and infection was determined by qPCR.
Results: The 6 subjects with highest gametocytemia were all infected with K13 (~49 – 1,749 female gametocytes/mL; 5 – 716 male gametocytes/mL). Two subjects received A/P prior to DFA/MFA and did not infect mosquitoes. The four subjects who did not receive A/P prior to DFA/MFA infected between 20% (18/89) and 97% (98/101) of mosquitoes by MFA, and between 3% (1/30) and 10% (3/30) of mosquitoes by DFA.
Conclusion: Artemisinin-resistant parasites are transmissible to mosquitoes after a single dose of artesunate. A/P appears to block transmission to mosquitoes, although is not gametocytocidal. The IBSM model could be used to test the transmission-blocking activity of licensed and investigational antimalarials.