Plasmodium sporozoite neutralization in the host skin

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Plasmodium sporozoites are the highly motile forms of malaria-causing parasites transmitted by the mosquito into the dermis of the host. Sporozoite motility is essential to access the blood circulation and can be inhibited by antibodies against the circumsporozoite protein (CSP), the major sporozoite surface protein. Recently, the Amino lab discovered a novel mechanism by which anti-CSP antibodies directly kill sporozoites of rodent and human infecting Plasmodia. Cytotoxicity is dependent on parasite motility and secretion of a sporozoite perforin-like protein, both indispensable for the parasite progression in the host skin. Accordingly, protection in immunized mice was only observed following parasite inoculation into the skin by microinjection or mosquito bite, but not after intravascular injection of parasites. The Frischknecht lab has developed a range of new assays to investigate sporozoite motility including the deployment of laser tweezers and subtle mutagenesis of key motility proteins. Recently the Frischknecht lab has generated a series of parasite lines expressing different types of CSP as fusion proteins with GFP. Here we propose to combine our expertise, to (i) test the generality of the skin-dependent protective mechanism of anti-CSP antibodies using sporozoites harboring the CSP of rodent or human infecting Plasmodium spp; (ii) image and characterize quantitatively the way protective antibodies are neutralizing sporozoites in the skin using parasites expressing GFP-CSP fusion proteins and biophysical methods; (iii) identify antibodies against other sporozoite surface proteins that potentiate anti-CSP neutralization in the skin and (iv) develop an in vitro 3D environment to rapidly test if levels of protection in individuals that are naturally exposed to mosquitoes or were vaccinated with RTS,S/AS01 correlate with cytotoxic activity. The expected results (i) will help our understanding of how CSP mediates sporozoite infectivity, (ii) should lead to a better understanding of the way antibodies can directly kill a parasite and (iii) could improve the efficacy of vaccination based on CSP, either by providing an immune correlate of protection and/or by the addition of novel protective antigens targeting sporozoites in the skin.