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.
Reviewing Editor
- Elena Levashina, Max Planck Institute for Infection Biology, Germany
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.
Version history
- Received: February 9, 2017
- Accepted: May 10, 2017
- Accepted Manuscript published: May 16, 2017 (version 1)
- Version of Record published: June 14, 2017 (version 2)
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.
Metrics
-
- 3,068
- views
-
- 759
- downloads
-
- 61
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Plasmodium P36 determines host cell receptor usage during sporozoite invasion
eLife 6:e25903.
https://doi.org/10.7554/eLife.25903
Further reading
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
eLife has published papers on many tropical diseases, including malaria, Ebola, leishmaniases, Dengue and African sleeping sickness.
-
- Microbiology and Infectious Disease
In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis with cell growth and division. Although GpsB has been studied in several bacteria, the structure, function, and interactome of Staphylococcus aureus GpsB is largely uncharacterized. To address this knowledge gap, we solved the crystal structure of the N-terminal domain of S. aureus GpsB, which adopts an atypical, asymmetric dimer, and demonstrates major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive to Staphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed in Bacillus subtilis. In S. aureus, we show that these hinge mutants are less functional and speculate that the conformational flexibility imparted by the hinge region may serve as a dynamic switch to finetune the function of the GpsB complex and/or to promote interaction with its various partners. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-termini, thus coupling peptidoglycan synthesis to cell division. Taken together, the unique structure of S. aureus GpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB in S. aureus cell division.
