Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.
Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS) can induce strong protective immunity both in...
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2008-01-01
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doaj-2ea9f701540643ada32ede68110a521d2020-11-24T22:09:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-01-01310e354910.1371/journal.pone.0003549Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.Ben C L van SchaijkChris J JanseGeert-Jan van GemertMelissa R van DijkAudrey GegoJean-Francois FranetichMarga van de Vegte-BolmerSamir YalaouiOlivier SilvieStephen L HoffmanAndrew P WatersDominique MazierRobert W SauerweinShahid M KhanDifficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium 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, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro 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 P. falciparum and rodent malaria Plasmodium 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.http://europepmc.org/articles/PMC2568858?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ben C L van Schaijk Chris J Janse Geert-Jan van Gemert Melissa R van Dijk Audrey Gego Jean-Francois Franetich Marga van de Vegte-Bolmer Samir Yalaoui Olivier Silvie Stephen L Hoffman Andrew P Waters Dominique Mazier Robert W Sauerwein Shahid M Khan |
spellingShingle |
Ben C L van Schaijk Chris J Janse Geert-Jan van Gemert Melissa R van Dijk Audrey Gego Jean-Francois Franetich Marga van de Vegte-Bolmer Samir Yalaoui Olivier Silvie Stephen L Hoffman Andrew P Waters Dominique Mazier Robert W Sauerwein Shahid M Khan Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. PLoS ONE |
author_facet |
Ben C L van Schaijk Chris J Janse Geert-Jan van Gemert Melissa R van Dijk Audrey Gego Jean-Francois Franetich Marga van de Vegte-Bolmer Samir Yalaoui Olivier Silvie Stephen L Hoffman Andrew P Waters Dominique Mazier Robert W Sauerwein Shahid M Khan |
author_sort |
Ben C L van Schaijk |
title |
Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
title_short |
Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
title_full |
Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
title_fullStr |
Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
title_full_unstemmed |
Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
title_sort |
gene disruption of plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2008-01-01 |
description |
Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium 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, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro 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 P. falciparum and rodent malaria Plasmodium 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. |
url |
http://europepmc.org/articles/PMC2568858?pdf=render |
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