Plasmodium sporozoite neutralization in the host skin (SporoSTOP)

Plasmodium sporozoites are the highly motile forms of malaria-causing parasites transmitted by the mosquito into the dermis of the mammalian host. Sporozoite motility is essential to access the blood circulation and can be inhibited by antibodies against the major protein of the sporozoite surface, the circumsporozoite protein (CSP). 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 green flouresence protein (GFP). The expected results (i) will help the 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.

Project details

Combination of Interventions
Genetics and Genomics
Immunology

Mar 2020 — Mar 2023

$233,759

France