Can we stop malaria parasites in the skin?

Abstract

Background Since the discovery of malaria transmission by mosquitoes, it was assumed that the parasites are injected directly into the blood stream. However, indirect experiments [1] and direct microscopic observations using mice as hosts and fluorescent rodent malaria species showed that the parasites are instead injected into the skin. These Plasmodium sporozoites then migrate rapidly through the dermis and enter blood or lymph vessels [2]. Stopping sporozoite motility also halts infection [3]. We aim at understanding the mechanisms that drive sporozoite motility and identify drug-like compounds that stop parasite locomotion. To this end, we have adapted and developed new methods including a screening pipeline to test small molecules that could interfere with motility and thus stop Plasmodium transmission at the skin stage [4,5]. Materials and methods A screening pipeline was developed that allowed medium-throughput assessment of small molecules as possible inhibitors of sporozoite motility in vitro. This was followed by in vivo testing during transmission from mosquito to mouse. Results We tested over 200 compounds selected from a library of drugs approved by the Federal Drug Administration for their potential to interfere with motility. We identified two molecules that inhibited in vitro motility in the nano-molar range. When these two compounds were tested during the transmission by mosquitoes, an ectopically applied drug resulted in a decrease of transmission efficiency while an orally given drug showed no effect on transmission at non-toxic doses.