Proteome Wide Study of Host-Parasite Interactions in Malaria Infections

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

The programme aims to capture the relationships among the multiple sets of components that define the host-parasite interaction during a malaria infection. |The work relies on the use of both experimental techniques that take a snapshot of the state of the infection and computational methods. Identification of these processes is essential for understanding the different severe malaria clinical presentations and provides relevant information for the development of new diagnostic tests and therapeutic strategies.

Technical Summary

Biomedical research in the post -omic age is currently influenced by systems biology approaches. The feasibility of capturing context-dependant molecular data of the components of an organism provides us with a view into the complex interactions that occur between a pathogen and its host.||Current malaria -omic information is primarily focused on the parasites molecular components. However, this information does not capture the way in which molecular components of both host and parasite interact to establish a specific disease state.||This programme aims to identify sets of molecules involved in specific pathogenic processes such as cerebral malaria and severe malarial anaemia. This programme also intends to extend our approach to examine a range of clinical presentations of human and mouse malaria infections and scenarios such as TB-malaria-HIV co-infections.||The programme has at its centre the study of the molecular basis of human malaria infections using mass spectrometry methods for high-throughput study of complex protein mixtures and computational analysis of the profiles obtained. State-of-the-art mass spectrometry (e.g. Surface-Enhanced Laser Desorption-Ionization Time-of-Flight SELDI-ToF) is used to capture a snapshot of the molecular components involved in a particular state of malarial infection. Computational and biochemical analysis of these complex profiles will allow us to identify molecular components and relationships among them that may provide an understanding of the pathological processes of malaria infection. Our results in the tuberculosis field showed that serum proteome profiling can provide disease-specific molecular proteome fingerprints reflecting host-pathogen interactions (Fernandez-Reyes, Agranoff et al. 2006). Moreover, our findings are the basis of diagnostic methods currently going into the patenting and validation process.||This systems biology programme relies on an tight integration of clinical, in vitro, in vivo and in silico work:|- Proteomic fingerprinting of serum, plasma, cerebro spinal fluid, bone marrow and urine from human and mouse malaria infections.|- Development and deployment of integrative statistical computational methods for the analysis of proteome fingerprints and post omic data.|- Identification of sets of molecules defining specific pathogenic processes such as severe malaria anaemia.|- Functional analysis of identified molecular components and evaluation of their possible use in diagnosis and/or therapeutics.|- Analysis of protein-protein interactions between identified host-pathogen molecules.
 
Title Collaboration with Street Art artist to use it as a media to engage the public in global health problems such as Malaria and TB 
Description We have been using street art at permitted locations across London touching in some awareness of TB and Malaria 
Type Of Art Artwork 
Year Produced 2014 
Impact Other artist became engaged and are now part of a network of street artist that will seek funding to explore further the use of this art form for increasing global health awareness 
 
Description G6PD screening in holoendemic malaria area attending tertiary care
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact The routine screen has had an impact on training and the paediatric care of the tertiary hospital
 
Description Iron supplementation in childhood severe malaria
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact The impact on tertiary care of severe malaria cases has been influenced by our research to an extend that instantiated a national review of the guidelines for iron supplementation in children with severe presentations of malaria. We have shown molecular evidence that supplementation in these cases is not required
 
Description Malaria Screening at University College Hospital Ibadan, Nigeria
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact We have design and deploy malaria screening quality control protocols that are in use in the UCH Ibadan and are also the backbone of our current malaria proteomics research project. This has an impact on malaria treatment and therefore in the disease outcome and rational administration of antimalarials. We have also introduced new methods for data acquisition in the complex hospital setting this has had a tremendous impact in care to the patient, clinicians and technicians training as well as malaria research in the Paediatric Department
 
Description case-control study severe malaria
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact The case-control study of severe malaria based in a tertiary hospital has had a tremendous impact on training at all levels from nurses to medical trainees. Sample collection protocols have introduced clear standards that have had an impact in patient care
 
Description EVIMALAR European Network of Excellence in Malaria Research
Amount £300,000 (GBP)
Organisation EVIMalaR 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2012 
End 02/2015
 
Title Active TB diagnostic test 
Description We have obtained serum proteomic signatures that discriminate Active Tuberculosis with diagnostic accuracy over 90%. We have discover set of biomarkers that are into the validation phase 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact Patent applied for May 2005. revenue share agreement with St George's Hospital, University of London 
 
Title Active TB plasma biomarker 
Description We have discovered a novel plasma biomarker of active tuberculosis. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact We are in the process to publish our results. We are planing to move this biomarker forward to the clinic 
 
Title Estimation of biomarkers using iterated weighted kernel functions 
Description We developed a new algorithm to estimate relevant biomarkers on data such proteomic or microarray profiles. We provide the software for academic users for several biomarker discovery projects 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Several groups are using our software to select biomarkers on their data. 
 
Title SCCA software 
Description SCCA is a new algorithm developed with colleagues at Department of Computer Science UCL London (Prof. John Shawe-Taylor) and in Finland (Dr Juho Rouso) 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact We distribute the software via request to the senior authors of the software that is used for biomarker discovery. 
 
Title discovery of haptoglobin polymorphisms associated with severe malarial anaemia 
Description discovery of haptoglobin polymorphism that is associated with low levels of plasma haptoglobin 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2016 
Provided To Others? Yes  
Impact our finding has now prompted a prospective large clinical validation study 
 
Title large case-control study of childhood severe malaria 
Description As part of the case-control study of childhood severe malaria we have collected serum, plasma, urine and csf on 3000 recruited patients. This is one of the largest and comprehensive malaria sample set currently available. Furthermore, it is one of the unique well clinically characterised set. 
Type Of Material Biological samples 
Provided To Others? No  
Impact We have now have discover markers associated with the pathogenesis of childhood severe malaria 
 
Title plasma biomarkers of severe childhood malaria 
Description we have validated a panel of protein plasma biomarkers for diagnosis, progression and outcome of childhood severe malaria 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2015 
Provided To Others? Yes  
Impact our validate panel is now deployed for clinical validation in tertiary care in sub-Saharan Africa urban areas of Nigeria 
 
Title Case-Control Severe Malaria Study Clinical Database 
Description Database of large case-control study focused on severity biomarker discovery SQL database with clinical, laboratory and experimental data 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact This large study is producing new findings of molecules that correlate with childhood severe malaria 
 
Description Biomarker Discovery for Diagnosis of Active Tuberculosis 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed on clinical study design and sample collection protocols. Proteomic experiments have been carried out in my laboratory BioSafety Containment 3 room using our SELDI-ToF mass spectrometer. We also designed and implemented the complex statistical analysis framework to discover biomarkers of TB infection from proteomic data.
Collaborator Contribution access to clinical samples and proteomics platformsaccess to clinical samples
Impact Lancet Paper (2006) PubMed ID 16980117
 
Description Biomarker Discovery for Diagnosis of Active Tuberculosis 
Organisation St George's University of London
Department Department of Cellular and Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed on clinical study design and sample collection protocols. Proteomic experiments have been carried out in my laboratory BioSafety Containment 3 room using our SELDI-ToF mass spectrometer. We also designed and implemented the complex statistical analysis framework to discover biomarkers of TB infection from proteomic data.
Collaborator Contribution access to clinical samples and proteomics platformsaccess to clinical samples
Impact Lancet Paper (2006) PubMed ID 16980117
 
Description Computational Analysis of Complex Biological Patterns 
Organisation University College London
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution We design algorithms and analysis frameworks in close relation to computational statistic theoreticians. My laboratory provides both the applied domain specific computational expertise and the relevant datasets that represent the biomedical hypothesis of interest.
Collaborator Contribution Access to novel computational statistics methods for the analysis of complex biological datasets such as proteomics
Impact PubMed ID 16980117 PubMed ID 18509521
 
Description Immuno Proteomics of Severe Malaria 
Organisation Karolinska Institute
Department Department of Microbiology, Tumour and Cell Biology
Country Sweden 
Sector Academic/University 
PI Contribution We provided samples from our case-control study of severe malaria
Collaborator Contribution They have provided a library of over 10,000 antibodies to human plasma proteins for a large scale screen. They have provided also a post-doctoral scientist to carry out the work.
Impact We have now discovered a panel of biomarkers of malaria severe disease. We are now writing a manuscript with the main findings and we plan to move forward a panel of severity biomarkers in the near future
Start Year 2011
 
Description Immuno Proteomics of Severe Malaria 
Organisation Science for Life Laboratory
Country Sweden 
Sector Academic/University 
PI Contribution We provided samples from our case-control study of severe malaria
Collaborator Contribution They have provided a library of over 10,000 antibodies to human plasma proteins for a large scale screen. They have provided also a post-doctoral scientist to carry out the work.
Impact We have now discovered a panel of biomarkers of malaria severe disease. We are now writing a manuscript with the main findings and we plan to move forward a panel of severity biomarkers in the near future
Start Year 2011
 
Description Latent Tuberculosis Biomarker Discovery 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed on clinical study design and sample collection protocols. Proteomic experiments have been carried out in my laboratory BioSafety Containment 3 room using our SELDI-ToF mass spectrometer. We also designed and implemented the complex statistical analysis framework to discover biomarkers of TB infection from proteomic data.
Collaborator Contribution access to clinical samples
Impact We have concluded sample collection of Latent TB cases in Peru over a period of two years. We now generated proteomic signatures that discriminate the Latent TB cases and current efforts are focus on determining a subset of these proteins to be pipelined into the biomarker validation phase.
Start Year 2007
 
Description Proteome-Wide Discovery of Host-Parasite Interactions During Severe Malaria 
Organisation University of Ibadan
Department Department of Paediatrics
Country Nigeria 
Sector Academic/University 
PI Contribution I have design the case-control study to discovery potential proteomic biomarkers of severity in malaria infections. The work is focused on Severe Malaria Anaemia and Cerebral Malaria. My research team designs and implements all the proteomics data generation from clinical specimens in our Bio Safety Level 3 room. My computational research team designs and implements complex computational statistics frameworks to analyse proteome patterns on these severe forms of malaria.
Collaborator Contribution Assignment of 2 Paediatrics Registrars for Project Sample Collection Assignment of a malaria laboratory technician. Assignment of one project data manager. Clinical and laboratory facilities at Hospital Site Access to severe malaria clinical cases and outpatient clinics Clinical Sample Collection
Impact This partnership has founded the Childhood Malaria Research Unit based at the University College Hospital Ibadan Nigeria. We have concluded the case-control recruitment for the discovery part of the project with 2000 individuals recruited over a period of three years.
Start Year 2006
 
Title Active TB diagnostic test 
Description We have discovered the serum proteome pattern that discriminate Active Tuberculosis. We have postulated a set of biomarkers from this profile to be taken to a biomarker validation pipeline. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2006
Development Status Actively seeking support
Impact Diagnostic of Active Tuberculosis is a challenging problem on Global Health, we have provided an alternative and reliable method to detect the disease process that does not requires to wait for 3 weeks as the sputum culture method. 
 
Title Relevant variable selection for large -omics datasets WKIDEA Machine Learning Software 
Description A machine learning to discovery relevant variable of multidimensional biological datasets 
Type Of Technology Software 
Year Produced 2009 
Open Source License? Yes  
Impact it is a stablished method to discover relevant combination of variable in multidimensional biological datasets 
 
Title Sparse Canonical Correlation Analysis Software 
Description SCCA is a novel biomarker discovery algorithm that allow the correlation of multivariate data against multivariate clinical complex phenotypes 
Type Of Technology Software 
Year Produced 2013 
Open Source License? Yes  
Impact We have now been involved in analysing datasets from several communicable diseases such as RSV, TB and Malaria 
 
Description School Visits - Ibadan Nigeria 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact We engage with schools in Ibadan centre to do malaria parasite screening in healthy children. We do disease awareness, explain results to parents, teachers and children. We explain how the research will have an impact in predicting what children may develop severe presentations of the malaria infection

Several schools contact us to provide regular screening and awareness sessions as well as discussion to parents and teachers in the Ibadan area.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
 
Description Vaccination Clinics 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Parents of children attending well children vaccination clinics attend for routine vaccinations

Parents are interested to get the children blood group and sickle trait results that are carried out when the children is recruited into the malaria case-control study
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016