Abstract
Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface1. Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus2, is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.
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Acknowledgements
We thank J. Chaker, I. Casal and K. Farhati for technical assistance. The monoclonal antibody against P. yoelii CSP (NYS1) was provided by Y. Charoenvit (Naval Medical Research Center, Silver Spring, Maryland), and monoclonal antibody against P. falciparum CSP (E9) by G. Pluschke (Swiss Tropical Institute, Basel, Switzerland). This work was supported in part by grants from Association Nouvelle Recherche Biomédicale and Institut de Cancérologie et Immunogénétique, and by US National Institutes of Health grant #AI45900.
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Silvie, O., Rubinstein, E., Franetich, JF. et al. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nat Med 9, 93–96 (2003). https://doi.org/10.1038/nm808
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DOI: https://doi.org/10.1038/nm808
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