Cell Traversal Activity Is Important for Plasmodium falciparum Liver Infection in Humanized Mice

Annie S P Yang; Matthew T O'Neill; Charlie Jennison; Sash Lopaticki; Cody C Allison; Jennifer S Armistead; Sara M Erickson; Kelly L Rogers; Andrew M Ellisdon; James C Whisstock; Rebecca E Tweedell; Rhoel R Dinglasan; Donna N Douglas; Norman M Kneteman; Justin A Boddey

doi:10.1016/j.celrep.2017.03.017

Cell Traversal Activity Is Important for Plasmodium falciparum Liver Infection in Humanized Mice

Cell Rep. 2017 Mar 28;18(13):3105-3116. doi: 10.1016/j.celrep.2017.03.017.

Authors

Affiliations

¹ 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.
² Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.
³ 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.
⁴ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁵ Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada.
⁶ 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.

PMID: 28355563
DOI: 10.1016/j.celrep.2017.03.017

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.

Keywords: SPECT; genetics; hepatocyte; invasion; malaria; motility; perforin; sporozoite; transmission; virulence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement*
Hepatocytes / parasitology
Hepatocytes / pathology
Humans
Liver / parasitology*
Liver / pathology*
Malaria, Falciparum / parasitology*
Malaria, Falciparum / pathology*
Mice, SCID
Mutation / genetics
Parasites / metabolism
Plasmodium falciparum / physiology*
Protozoan Proteins / metabolism
Sporozoites / metabolism

Substances

Protozoan Proteins