title: AMA1 and MAEBL are important for Plasmodium falciparum sporozoite infection of the liver.
abstract: The malaria sporozoite injected by a mosquito migrates to the liver by traversing host cells. The sporozoite also traverses hepatocytes before invading a terminal hepatocyte and developing into exoerythrocytic forms. Hepatocyte infection is critical for parasite development into merozoites that infect erythrocytes, and the sporozoite is thus an important target for antimalarial intervention. Here, we investigated two abundant sporozoite proteins of the most virulent malaria parasite Plasmodium falciparum and show that they play important roles during cell traversal and invasion of human hepatocytes. Incubation of P. falciparum sporozoites with R1 peptide, an inhibitor of apical merozoite antigen 1 (AMA1) that blocks merozoite invasion of erythrocytes, strongly reduced cell traversal activity. Consistent with its inhibitory effect on merozoites, R1 peptide also reduced sporozoite entry into human hepatocytes. The strong but incomplete inhibition prompted us to study the AMA-like protein, merozoite apical erythrocyte-binding ligand (MAEBL). MAEBL-deficient P. falciparum sporozoites were severely attenuated for cell traversal activity and hepatocyte entry in vitro and for liver infection in humanized chimeric liver mice. This study shows that AMA1 and MAEBL are important for P. falciparum sporozoites to perform typical functions necessary for infection of human hepatocytes. These two proteins therefore have important roles during infection at distinct points in the life cycle, including the blood, mosquito, and liver stages.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Annie S P
authors.initials: ASP
authors.lastname: Yang
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: O'Neill
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Erickson
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Donna N
authors.initials: DN
authors.lastname: Douglas
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Justin A
authors.identifier: 0000-0001-7322-2040
authors.initials: JA
authors.lastname: Boddey
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000953:Antigens, Protozoan / Q000235:genetics; D002460:Cell Line; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D022781:Hepatocytes / Q000469:parasitology*; D006801:Humans; D008099:Liver / Q000469:parasitology; D016778:Malaria, Falciparum / Q000469:parasitology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D052940:Merozoites / Q000254:growth & development*; D051379:Mice; D016513:Mice, SCID; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics; D034101:Sporozoites / Q000254:growth & development*
chemical_list: D000953:Antigens, Protozoan; C468522:MAEBL protein, Plasmodium falciparum; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C090077:apical membrane antigen I, Plasmodium
keywords: cell traversal; hepatocyte; humanized mice; invasion; malaria; sporozoite