Targeting Malaria Transmission: A Transdisciplinary Approach

Abstract

To achieve malaria elimination, great emphasis must be put on targeting the parasite’s transmissible stages, so that along with effective treatment of clinical malaria caused by asexual stages, complete interruption of the life cycle can be achieved. However, the sustainable goal of interrupting malaria transmission is more complex than previously thought, as demonstrated by the many failed attempts to eradicate the parasite. One of the various reasons why interrupting malaria transmission is challenging is that the transmissible gametocytes are resilient and complex in nature. The adaptable nature of the malaria parasite suggests that enhanced gametocyte production is a response to adverse environments. Although gametocytes are constitutively formed at a very low frequency, mounting evidence supports that external factors modulate the rate of sexual conversion by increasing or decreasing gametocyte production. However, whether the most effective antimalarial drug artemisinin can stimulate sexual conversion, which would result in increased production of functional gametocytes in P. falciparum, remains to be clarified both under laboratory culture conditions and in field settings. We addressed this research question by first creating a robust assay that measures the sexual conversion rate. With our new reporter parasite lines, we were able to shorten the sexual conversion assay, dispensing the need for anti-asexual multiplication compounds. Our new gexp02 promoter-based lines showed the ability to distinguish sexual rings at a single-cell level. We then tested the impact of artemisinin on sexual conversion and the transmissibility of artemisinin-induced gametocytes to mosquitoes. Our results revealed that exposure to subcurative doses of DHA at the trophozoite stage, but not at the ring stage, upregulated the expression of pfap2-g, the master regulator of sexual commitment, and increased the rate of sexual conversion and the total gametocyte numbers. Gametocytes from artemisinin-induced cultures were infectious to the mosquito vector. We extended the scope of our study beyond the laboratory format by looking into how treatment affects the sexual conversion of parasites from naturally-infected patients. Here we observed a clear upregulation of transcript levels for pfap2-g and other sexual ring biomarkers after treatment, suggesting an induced sexual conversion. Artemisinin resistant parasites (PfK13 mutants) from Vietnam showed significantly lower levels of pfap2-g induction, whereas sensitive parasites from African cohorts displayed higher pfap2-g induction immediately after treatment. Lastly, we examined the malaria perception of the community in the Magude district of Southern Mozambique. We identified potential constraints and opportunities that might affect the deployment of interventions for the malaria elimination initiative. Malaria awareness, trust in health institutions and openness for new chemoprophylaxis may positively influence the elimination effort. A lack of awareness of asymptomatic carriers, inadequate understanding of residual transmission and barriers to care-seeking might jeopardize the uptake of malaria interventions.