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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.00127

The Selection of a Hepatocyte Cell Line Susceptible to Plasmodium falciparum Sporozoite Invasion That is Associated With Expression of Glypican-3

  • 1Johns Hopkins University, United States
  • 2Emerging Pathogens Institute, University of Florida, United States
  • 3W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, United States
  • 4Walter Reed Army Institute of Research, United States
  • 5Department of Mathematics and Computer Science, Faculty of Science, University of Southern Denmark, Denmark
  • 6Mississippi State University, United States
  • 7Universität München, Germany

In vitro studies of liver stage (LS) development of the human malaria parasite Plasmodium falciparum are technically challenging; therefore, fundamental questions about hepatocyte receptors for invasion that can be targeted to prevent infection remain unanswered. To identify novel receptors and to further understand human hepatocyte susceptibility to P. falciparum sporozoite invasion, we created an optimized in vitro system by mimicking in vivo liver conditions and using the subcloned HC-04.J7 cell line that supports mean infection rates of 3-5% and early development of P. falciparum exoerythrocytic forms—a 3- to 5-fold improvement on current in vitro hepatocarcinoma models for P. falciparum invasion. We juxtaposed this invasion-susceptible cell line with an invasion-resistant cell line (HepG2) and performed comparative proteomics and RNA-seq analyses to identify host cell surface molecules and pathways important for sporozoite invasion of host cells. We identified and investigated a hepatocyte cell surface heparan sulfate proteoglycan, glypican-3, as a putative mediator of sporozoite invasion. We also noted the involvement of pathways that implicate the importance of the metabolic state of the hepatocyte in supporting LS development. Our study highlights important features of hepatocyte biology, and specifically the potential role of glypican-3, in mediating P. falciparum sporozoite invasion. Additionally, it establishes a simple in vitro system to study the LS with improved invasion efficiency. This work paves the way for the greater malaria and liver biology communities to explore fundamental questions of hepatocyte-pathogen interactions and extend the system to other human malaria parasite species, like P. vivax.

Keywords: Malaria, Plasmodium falciparum, Liver stage, in vitro model, omics, Glypican (GPC) 3, hepatocyte

Received: 13 Oct 2018; Accepted: 21 Jan 2019.

Edited by:

Celio G. Freire-de-Lima, Federal University of Rio de Janeiro, Brazil

Reviewed by:

Miguel Prudêncio, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal
Rodrigo A. López-Muñoz, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Chile  

Copyright: © 2019 Tweedell, Tao, Hamerly, Robinson, Larsen, Grønning, Norris, King, Law, Baumbach, Bergmann-Leitner and Dinglasan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Rebecca E. Tweedell, Johns Hopkins University, Baltimore, United States, rtweede1@jhmi.edu
Dr. Rhoel R. Dinglasan, Emerging Pathogens Institute, University of Florida, Gainesville, 32608, Florida, United States, rdinglasan@epi.ufl.edu