Anti-CD81 but not anti-SR-BI blocks Plasmodium falciparum liver infection in a humanized mouse model

OBJECTIVES: Plasmodium falciparum sporozoites, deposited in the skin by infected Anopheles mosquitoes taking a blood meal, cross the endothelium of skin capillaries and travel to the liver where they traverse Kupffer cells and hepatocytes to finally invade a small number of the latter. In hepatocytes, sporozoites replicate, differentiate and give rise to large numbers of merozoites that are released into the bloodstream where they invade red blood cells, thus initiating the symptomatic blood stage. Using in vitro systems and rodent models, it has been shown that the hepatocyte receptors CD81 and scavenger receptor type B class I (SR-BI) play a pivotal role during sporozoite invasion. We wanted to evaluate whether these two entry factors are genuine drug targets for the prevention of P. falciparum infection in humans. METHODS: Immunodeficient mice of which the liver is largely repopulated by human hepatocytes were treated with monoclonal antibodies blocking either CD81 or SR-BI 1 day prior to challenge with infected mosquitoes. P. falciparum infection of the liver was demonstrated using a qPCR assay. RESULTS: In human liver chimeric mice, an antibody directed against CD81 completely blocked P. falciparum sporozoite invasion while SR-BI-specific monoclonal antibodies did not influence in vivo infection. CONCLUSIONS: These observations confirm the role of CD81 in liver-stage malaria and question that of SR-BI. CD81 might be a valuable drug target for the prevention of malaria.