Plasmodium P36 determines host cell receptor usage during sporozoite invasion
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, France
- Mahidol University, Thailand
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, France
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, France
- INSERM, U935, France
- Centre d'Immunologie et des Maladies Infectieuses, U1135, ERL8255, France
Abstract
Plasmodium sporozoites, the mosquito-transmitted forms of the malaria parasite, first infect the liver for an initial round of replication before the emergence of pathogenic blood stages. Sporozoites represent attractive targets for antimalarial preventive strategies, yet the mechanisms of parasite entry into hepatocytes remain poorly understood. Here we show that the two main species causing malaria in humans, Plasmodium falciparum and Plasmodium vivax, rely on two distinct host cell surface proteins, CD81 and the Scavenger Receptor BI (SR-BI), respectively, to infect hepatocytes. By contrast, CD81 and SR-BI fulfil redundant functions during infection by the rodent parasite P. berghei. Genetic analysis of sporozoite factors reveals the 6-cysteine domain protein P36 as a major parasite determinant of host cell receptor usage. Our data provide molecular insights into the invasion pathways used by different malaria parasites to infect hepatocytes, and establish a functional link between a sporozoite putative ligand and host cell receptors.
Article and author information
Author details
Funding
European Commission
- Dominique Mazier
- Thomas F Baumert
- Olivier Silvie
Agence Nationale de la Recherche
- Mirjam B Zeisel
- Dominique Mazier
- Thomas F Baumert
- Olivier Silvie
National Centre for the Replacement, Refinement and Reduction of Animals in Research
- Olivier Silvie
Conseil Régional, Île-de-France
- Giulia Manzoni
- Marion Gransagne
Wellcome
- François Nosten
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was conducted in strict accordance with the Directive 2010/63/EU of the European Parliament and Council 'On the protection of animals used for scientific purposes'. The protocol was approved by the Charles Darwin Ethics Committee of the University Pierre et Marie Curie, Paris, France (permit number Ce5/2012/001).
Human subjects: Blood samples were obtained from P. vivax-infected individuals attending the Shoklo Malaria Research Unit (SMRU) clinics on the western Thailand-Myanmar border, after signature of a consent form. Primary human hepatocytes were isolated from healthy parts of human liver fragments, which were collected from adult patients undergoing partial hepatectomy (Service de Chirurgie Digestive, Hépato-Bilio-Pancréatique et Transplantation Hépatique, Groupe Hospitalier Pitie-Salpetriere, Paris, France). The collection and use of this material were undertaken in accordance with French national ethical guidelines under Article L. 1121-1 of the 'Code de la Santé Publique', and approved by the Institutional Review Board (Comité de Protection des Personnes) of the Centre Hospitalo-Universitaire Pitié-Salpetriere, Assistance Publique-Hopitaux de Paris, France.
Copyright
© 2017, Manzoni et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Plasmodium P36 determines host cell receptor usage during sporozoite invasion
eLife 6:e25903.
https://doi.org/10.7554/eLife.25903
Further reading
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- Epidemiology and Global Health
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The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light on the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using the CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggests that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.
