title: Cell Traversal Activity Is Important for Plasmodium falciparum Liver Infection in Humanized Mice.
abstract: Malaria sporozoites are deposited into the skin by mosquitoes and infect hepatocytes. The molecular basis of how Plasmodium falciparum sporozoites migrate through host cells is poorly understood, and direct evidence of its importance in vivo is lacking. Here, we generated traversal-deficient sporozoites by genetic disruption of sporozoite microneme protein essential for cell traversal (PfSPECT) or perforin-like protein 1 (PfPLP1). Loss of either gene did not affect P. falciparum growth in erythrocytes, in contrast with a previous report that PfPLP1 is essential for merozoite egress. However, although traversal-deficient sporozoites could invade hepatocytes in vitro, they could not establish normal liver infection in humanized mice. This is in contrast with NF54 sporozoites, which infected the humanized mice and developed into exoerythrocytic forms. This study demonstrates that SPECT and perforin-like protein 1 (PLP1) are critical for transcellular migration by P. falciparum sporozoites and demonstrates the importance of cell traversal for liver infection by this human pathogen.
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Annie S P
authors.initials: ASP
authors.lastname: Yang
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: O'Neill
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Charlie
authors.initials: C
authors.lastname: Jennison
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Cody C
authors.initials: CC
authors.lastname: Allison
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Armistead
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Erickson
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Rogers
authors.affiliation: Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3800, VIC, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton 3800, VIC, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Ellisdon
authors.affiliation: Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3800, VIC, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton 3800, VIC, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Tweedell
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Rhoel R
authors.initials: RR
authors.lastname: Dinglasan
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Donna N
authors.initials: DN
authors.lastname: Douglas
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3052, VIC, Australia. Electronic address: boddey@wehi.edu.au.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Boddey
mesh_terms: D000818:Animals; D002465:Cell Movement; D022781:Hepatocytes / Q000469:parasitology / Q000473:pathology; D006801:Humans; D008099:Liver / Q000469:parasitology* / Q000473:pathology*; D016778:Malaria, Falciparum / Q000469:parasitology* / Q000473:pathology*; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D010271:Parasites / Q000378:metabolism; D010963:Plasmodium falciparum / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism; D034101:Sporozoites / Q000378:metabolism
chemical_list: D015800:Protozoan Proteins
keywords: SPECT; genetics; hepatocyte; invasion; malaria; motility; perforin; sporozoite; transmission; virulence