title: Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity.
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 surface. 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 virus, 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.
authors.affiliation: INSERM U511 Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Silvie
authors.forename: Eric
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Franetich
authors.forename: Michel
authors.initials: M
authors.lastname: Prenant
authors.forename: Elodie
authors.initials: E
authors.lastname: Belnoue
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Wijnand
authors.initials: W
authors.lastname: Eling
authors.forename: Shoshana
authors.initials: S
authors.lastname: Levy
authors.forename: Claude
authors.initials: C
authors.lastname: Boucheix
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000469:parasitology*; D006801:Humans; D008288:Malaria / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000469:parasitology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010963:Plasmodium falciparum / Q000502:physiology*; D010967:Plasmodium yoelii / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D034101:Sporozoites / Q000502:physiology*; D060225:Tetraspanin 28; D060245:Tetraspanin 29
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C554869:CD9 protein, human; C554799:Cd81 protein, mouse; C554870:Cd9 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D060225:Tetraspanin 28; D060245:Tetraspanin 29; C041595:circumsporozoite protein, Protozoan