Abstract
BackgroundAnti-malarial compounds have not yet been identified that target the first obligatory step of infection in humans: the migration of Plasmodium sporozoites in the host dermis. This movement is essential to find and invade a blood vessel in order to be passively transported to the liver. Here, an imaging screening pipeline was established to screen for compounds capable of inhibiting extracellular sporozoites.MethodsSporozoites expressing the green fluorescent protein were isolated from infected Anopheles mosquitoes, incubated with compounds from two libraries (MMV Malaria Box and a FDA-approved library) and imaged. Effects on in vitro motility or morphology were scored. In vivo efficacy of a candidate drug was investigated by treating mice ears with a gel prior to infectious mosquito bites. Motility was analysed by in vivo imaging and the progress of infection was monitored by daily blood smears.ResultsSeveral compounds had a pronounced effect on in vitro sporozoite gliding or morphology. Notably, monensin sodium potently affected sporozoite movement while gramicidin S resulted in rounding up of sporozoites. However, pre-treatment of mice with a topical gel containing gramicidin did not reduce sporozoite motility and infection.ConclusionsThis approach shows that it is possible to screen libraries for inhibitors of sporozoite motility and highlighted the paucity of compounds in currently available libraries that inhibit this initial step of a malaria infection. Screening of diverse libraries is suggested to identify more compounds that could serve as leads in developing ‘skin-based’ malaria prophylactics. Further, strategies need to be developed that will allow compounds to effectively penetrate the dermis and thereby prevent exit of sporozoites from the skin.
Highlights
Anti-malarial compounds have not yet been identified that target the first obligatory step of infection in humans: the migration of Plasmodium sporozoites in the host dermis
Sporozoites associate with blood vessels and enter the blood stream whereby they passively drift before invading hepatocytes [29, 30, 43,44,45]
The Malaria Box is a library of approximately 400 compounds that were initially identified as hits of Plasmodium falciparum asexual blood stage development [10] and later screened for effects at other life cycle stages as well as different pathogens [9]
Summary
Anti-malarial compounds have not yet been identified that target the first obligatory step of infection in humans: the migration of Plasmodium sporozoites in the host dermis. This movement is essential to find and invade a blood vessel in order to be passively transported to the liver. Sporozoites form in oocysts within the mosquito vector and need their motility first to be released into the haemocoel of the insect [33], where they passively drift before actively invading salivary glands [34,35,36]. Sporozoites associate with blood vessels and enter the blood stream whereby they passively drift before invading hepatocytes [29, 30, 43,44,45]
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