Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes

van Schaijk, B. C. L. et al. (2008) Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. PLoS ONE, 3(10), e3549. (doi: 10.1371/journal.pone.0003549)

Abstract

Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated <i>Plasmodium</i> parasites. Immunizations with sporozoites that are attenuated by radiation (RAS) can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS) depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, <i>p52</i>, in <i>P. falciparum</i> an ortholog of the rodent parasite gene, <i>p36p</i>, which we had previously shown can confer long lasting protective immunity in mice. These <i>P. falciparum</i> P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes <i>in vitro</i> that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both <i>P. falciparum</i> and rodent malaria <i>Plasmodium</i> species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use.

• Item Type: Articles
• Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Waters, Professor Andy
• Authors: van Schaijk, B. C. L., Janse, C. J., van Gemert, G. J., van Dijk, M. R., Gegoc, A., Franetich, J. F., van de Vegte-Bolmera, M., Yalaouic, S., Silvie, O., Hoffman, S. L., Waters, A. P., Mazier, D., Sauerwein, R. W., and Khan, S. M.
• Subjects: Q Science > QR Microbiology > QR180 Immunology; Q Science > QR Microbiology
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 01 January 2008
• Copyright Holders: © 2008 van Schaijk et al
• First Published: First published in PLoS ONE 2008 3(10): e3549
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher