Malaria parasite proteins and erythrocyte invasion

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Malaria is the most important vector borne disease and there is an urgent need for new methods to control it, for example the development of new drugs or vaccines. It is caused by a parasite that must invade and multiply within the bloods red cells to survive. At the same time this process causes the disease. By preventing red blood cell invasion both the multiplication of the parasite and the disease would be controlled. We are studying parasite surface proteins and others in specialised structures that facilitate this process of invasion. By understanding what proteins are involved in the parasite recognising and invading red blood cells it should be possible to develop strategies to control malaria. We have already shown that one of these proteins on the parasite surface is the target of antibodies that stop invasion and therefore it is a good vaccine candidate; recent work has confirmed the validity of this approach and points the way towards vaccine development. The work may also facilitate the identification of new targets for drugs against malaria, possibly leading to new products or applications and improved treatment.

Technical Summary

There is an urgent need to control malaria, which is caused by a parasite transmitted by mosquitoes. Our goal is to understand how this parasite multiplies in the human bloodstream, thereby causing the disease. The objectives are to understand erythrocyte invasion by the malaria parasite, focusing on the human parasite Plasmodium falciparum and the merozoite form that invades red blood cells. In particular the aims are (i) to define the role of a merozoite surface protein complex in invasion, and develop experimental vaccines based on these molecules, (ii) to investigate the importance of parasite organelle proteins in invasion, and (iii) to understand the molecular motor that drives the invasion process. The study of proteins on the merozoite surface has shown that a component of a multimolecular complex (largely formed by proteolytic processing of merozoite surface protein 1, MSP1) is the target of antibodies that prevent parasite invasion of erythrocytes, and this protein component is now one of the leading candidates for development as a vaccine against malaria. In collaboration with groups in Nigeria studies with human antibodies have reinforced this conclusion. Using a variety of methods, we have analysed the 3-dimensional structure of the protein and the fine specificity of the antibody reactivity, particularly those antibodies that inhibit invasion. This work has identified modified proteins that are more effective than the natural protein at inducing protective antibodies by immunisation, suggesting that they are particularly suitable for development into a malaria vaccine. Most recently we have shown the importance of the Fc region of the antibodies. Other polypeptides in the complex that are not derived from MSP1 are being characterised. One of them (MSP7) is tightly associated with MSP1 and we have examined its biosynthesis and maturation. In the apical organelles called rhoptries and micronemes, several sets of proteins have been investigated, using both human malaria and rodent malaria parasites. These proteins are ligands for receptor(s) on the surface of the host erythrocyte and are therefore directly involved in erythrocyte recognition and invasion. Another set of proteins is a quaternary complex of three large polypeptides. This rhoptry protein complex may also bind to red cells and could be involved after invasion in remodelling the red blood cell for the parasite to develop within. Recently we have shown that the expression of several of the genes coding for these proteins is under epigenetic control. Understanding the structure and function of these proteins may provide new targets to combat the malaria parasite. An unusual actomyosin motor located beneath the surface of the invasive form of the parasite drives it into the red cell. In collaboration with Justin Molloy and Claudia Veigel (Division of Physical Biochemistry) we are characterising the structure and function of this motor. We have already identified unusual features of the actin and shown that the motor is anchored in an inner membrane complex by a group of proteins of which one is acylated. We have identified inhibitors of one form of acylation. Inhibiting the function of the motor prevents invasion and therefore may be another point of attack using drugs to kill the parasite. The methods used include: analysis of parasite growth in vitro; analysis of protein biosynthetic pathways and function; application of expression systems to produce correct folded recombinant proteins for structural studies and to produce antibody reagents; immunochemical analysis of proteins; development of modified proteins as vaccine candidates; analysis of parasite genes and genome by cloning, sequence analysis and bioinformatic approaches.

Publications

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Abath FG (1995) A strategy to sequence repetitive DNA based on partial restriction enzyme cleavage. in Applied biochemistry and biotechnology

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Babon JJ (2007) Structural studies on Plasmodium vivax merozoite surface protein-1. in Molecular and biochemical parasitology

 
Description EU-India collaboration (Malsig)
Amount £159,360 (GBP)
Funding ID Health-2007-2.3.2-12-223044 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2009 
End 01/2012
 
Description EU-Intergrated Project-FP6-2006
Amount £109,354 (GBP)
Funding ID LSH-2005-037506 
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 12/2006 
End 11/2011
 
Description EU-Network of Excellence ( Evimalar)
Amount £90,423 (GBP)
Funding ID Health-2009-2.3.2-1-242095 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2009 
End 03/2015
 
Description EU-Specific Targeted Project-FP6-2007
Amount £130,159 (GBP)
Funding ID LHSP-CT-2006-036838 
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 01/2007 
End 12/2008
 
Description MRC Industry Collaboration Award
Amount £206,150 (GBP)
Funding ID G0900278 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2010 
End 05/2014
 
Description University of Notre Dame Subaward
Amount £730,909 (GBP)
Funding ID P01 HL078826 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2005 
End 08/2010
 
Title Pk parasites 
Description A simian malaria parasite cultured in human red blood cells and with very high transfection efficiency. 
Type Of Material Cell line 
Year Produced 2011 
Provided To Others? Yes  
Impact Awaiting primary publication 
 
Description BPRC 
Organisation Biomedical Primate Research Centre
Department Department of Parasitology
Country Netherlands 
Sector Academic/University 
PI Contribution Complementary interests in malaria vaccines
Collaborator Contribution Complementary interests in malaria vaccines
Impact 18550731, 17938224
 
Description Guys Hospital 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution provided the parasiology question.
Collaborator Contribution Provided ultrastructure technology
Impact 17097159, 18769730, 19428658
 
Description IBADAN 
Organisation University of Ibadan
Department Department of Zoology
Country Nigeria 
Sector Academic/University 
PI Contribution Provision of reagents and assays
Collaborator Contribution Provision of field data and samples
Impact 16055071, 199930613, 19081386, 20955565, 21326959
 
Description IMAXIO 
Organisation Imaxio SA
Country France 
Sector Private 
PI Contribution Biological model for malaria vaccine development
Collaborator Contribution Novel adjuvant technology
Impact 18474650, 18660818
 
Description Imperial Biology 
Organisation Imperial College London
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided reagents and expertise
Collaborator Contribution Establishment of protein arrays
Impact 15339842, 17510307
 
Description Imperial Chemistry 
Organisation Imperial College London
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Indentification of drug target
Collaborator Contribution Chemical expertise
Impact Peptide-based inhibitors, 18188474, 17714074, 18324715, 20174678
 
Description Jenner 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of reagents and know-how
Collaborator Contribution Vaccine development technology
Impact 18660818, 20713623, 21698193
 
Description LSHTM 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Faculty of Infectious and Tropical Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution provided reagents and expertise.
Collaborator Contribution Field oriented expertise.
Impact 16622227, 17510307, 19915077
 
Description MRCT 
Organisation MRC-Technology
Department MRCT Centre for Therapeutics Discovery (CTD)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Identified malaria parasite targets for new drug discovery and antibody development
Collaborator Contribution Partnership with antibody engineering and drug discovery groups
Impact Successful drug discovery programme.
 
Description MVDB, NIH 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Complementary parasite reagents and expertise
Collaborator Contribution Complementary protein expertise
Impact 15618165, 16988228, 18710865
 
Description Molecular Structure 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Parasitology question.
Collaborator Contribution Mass spectrometry and structure expertise
Impact 16516987, 18768477, 20472690
 
Description NMR Centre 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Provided the proteins of interest.
Collaborator Contribution NMR expertise
Impact 15641776, 17343930
 
Description Nanyang 
Organisation Nanyang Technological University
Country Singapore 
Sector Academic/University 
PI Contribution Complementary parasite expertise.
Collaborator Contribution Complementary parasite expertise.
Impact 116959335 8474651
 
Description Notre Dame 
Organisation University of Notre Dame
Department Centre for Rare and Neglected Diseases (CRND)
Country United States 
Sector Academic/University 
PI Contribution Identification of parasite proteins and their genes for study
Collaborator Contribution Development of animal models of severe malaria disease
Impact 21980474
 
Description Nottingham 
Organisation University of Nottingham
Department School of Biology Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided reagents and expertise
Collaborator Contribution Provided specific model
Impact 17511516, 19805526, 21781305, 20886115
 
Description PHYSICAL BIOCHEMISTRY 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Parasitology
Collaborator Contribution Biochemistry and enzymology
Impact 16431905, 18413861
 
Description Physical Biochemistry 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Expertise on the malaria parasite
Collaborator Contribution Provided expertise on motor proteins and biophysical charaterization of proteins.
Impact 15876372, 16337961, 16750579, 18768477,20826799, 22001249,Optical trapping studies
 
Description Sanger 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Defined the biological problem
Collaborator Contribution Provided microarray/bioinformatics analysis
Impact 17676953, 21379566
 
Description The Gambia 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Provided reagents and intellectual contribution
Collaborator Contribution Provided field-based resources.
Impact 16622227, 19758375, 22059995
 
Description WEHI 
Organisation The Walter and Eliza Hall Institute of Medical Research (WEHI)
Country Australia 
Sector Academic/University 
PI Contribution Parasite cell and molecular biology
Collaborator Contribution Parasite molecular biology
Impact 16321976, 17511516, 18820076
 
Title MSP1 
Description Malaria vaccine development 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Phase II clinical trials are in progress elsewhere 
 
Description Seminars 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Provided overview of activities to interested lay-people

Increased general level of awareness
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010