gms | German Medical Science

Since the discovery of malaria transmission by mosquitoes it was assumed that the parasites are injected into the blood. However, indirect experiments and direct microscopic observations using mice as hosts and rodent malaria species expressing fluorescent proteins 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. Stopping sporozoite motility has been shown to halt infection. We aim to understand the mechanisms that drive sporozoite motility and to stop it with drugs. To this end, we adapted and developed new methods including a screening pipeline to test small molecules that could interfere with motility and thus stop malaria transmission in the skin.

A screening pipeline was developed that allowed to rapidly assess if a small molecule is inhibiting sporozoite motility in vitro followed by in vivo testing during transmission from mosquito to mouse.

We tested over 200 substances 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 at a nano-molar level. When tested during the transmission by mosquitoes a topically applied drug resulted in a decrease of transmission efficiency, while an orally given drug showed no effect on transmission at non-toxic doses. This approach could be used to screen for further candidates for skin stage prophylactic intervention.