An analysis of ICAM-1 adhesion in P.falciparum malaria

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Grants and Contracts Support Office

Abstract

With 300 to 500 million infections worldwide every year, malaria ranks as one of the major infectious diseases of developing countries. The processes by which this disease progresses to severe symptoms are poorly understood but with 1-2 million deaths every year from malaria, mainly in children under five in sub-Saharan Africa, their elucidation is a priority. Of the four species of the human malaria parasites, Plasmodium falciparum is unique in being able to promote the attachment of infected red blood cells to cells lining small blood vessels in the host. It is thought that this adhesive property is associated with the development of life-threatening symptoms.
This study sets out to examine how malaria parasites from clinical samples bind to human cells and to understand the attributes of P.falciparum that allow it to do this. One of the problems is that unlike most pathogenic organisms, P.falciparum is able to stick to a range of host receptors so part of the question being addressed is whether one of these, intercellular adhesion molecule-1 (or ICAM-1) , is particularly involved in the progression to severe disease rather than the mild symptoms seen in most infections.
With the resources generated from the clinical study we will be able to examine the molecular events taking place during sequestration, leading to the identification of the binding site on the P.falciparum-infected red blood cell and the development of new interventions aimed at preventing severe malaria. By understanding how infected red blood cells and host cells interact, we can design chemicals that will interfere with this process for the treatment of acute malaria infection, but also we will be able to investigate whether children can be immunised against types of malaria parasites that cause severe disease. The latter ?anti-disease? strategy would reduce mortality from malaria while allowing people in malaria endemic countries to still develop the naturally-acquired immunity that protects them throughout their adult lives.
Both the Liverpool School of Tropical Medicine (LSTM) and Kenyan sites are commited to the involvement of people from developing countries in research, in terms of technology transfer and education and also in communicating their results to the community at large. Both have a strong and long-term commitment to ?promote improved health, particularly for people of the less developed countries in the tropics and sub-tropics? (LSTM Mission Statement).

Technical Summary

P.falciparum malaria is one of the three major infectious diseases of developing countries, causing over 1 million deaths per year and inflicting a heavy burden economically on some of the poorest regions in the world. Malaria is a complex disease, encompassing a number of severe syndromes such as malarial anaemia and host organ failure (including cerebral malaria). The basis for pathogenesis is not known but the unique ability of P.falciparum (amongst human malaria parasites) to cause sequestration of mature infected erythrocytes from the peripheral circulation by cytoadherence to small vessel endothelium is thought to be a major component. Our understanding of the molecular events involved in primary adhesion is relatively well developed but the relationship between specific receptor usage and disease is not. Data on this latter point have been conflicting but there are several lines of evidence that support ICAM-1 as having a role in pathogenesis.
The aims of this study are
? to analyse the role of ICAM-1 adhesion in causing severe malaria in children.
? to link this clinical study with a molecular analysis of the corresponding binding site for ICAM-1 on the parasite ligand PfEMP1, leading to the identification of a consensus for the binding site on PfEMP1
These will incorporate binding assays under static and flow conditions using protein and cell-based targets as well as molecular and bioinformatics techniques. This will allow us to evaluate the impact of ICAM-1-based, anti-adhesive interventions, by defining the prevalence of ICAM-1 binding in patient isolates and its association with severe disease and contribute to the development of anti-disease vaccines and drugs based on inhibition of cytoadherence through characterisation of the binding site on the infected erythrocyte.

Publications

10 25 50
 
Description Training of early stage researchers in Kenya
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Post-graduates have been trained through association with the study in Kenya.; One post-graduate researcher has gone on to do a PhD and another application has recently been made to an EU-funded scheme.
 
Description Wellcome Trust
Amount £190,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 09/2012
 
Description Wellcome Trust Project Grant (Early induction of pro-adhesive state by P.falciparum cytoadherence)
Amount £282,537 (GBP)
Funding ID 085391 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2008 
End 05/2011
 
Description Wellcome Trust Senior Investigator Award
Amount £1,500,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2016
 
Title Adhesion assay development 
Description Influence of mycoplasma infection in P.falciparum cultures on adhesion assays. 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Need to ensure screening for mycoplasma 
 
Title ICAM-1-binding IE 
Description New laboratory adapted P. falciparum isolates selected for binding to ICAM-1. 
Type Of Material Cell line 
Year Produced 2010 
Provided To Others? Yes  
Impact We are currently analysing the molecular and cell-biology signatures of these new parasite isolates. 
 
Description KEMRI-Kilifi 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Academic/University 
PI Contribution Adhesion assay training and scientific support for PhD students
Collaborator Contribution Joint PhD studentships
Impact No outputs as yet.
Start Year 2009
 
Description Community 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact 1. Links (and membership) with local Rotary organisation by lead researcher in Kenya. 2. Presentation to academics visiting the Kilifi site.

Strong relationship between local population in Kilifi with resreach unit.
Year(s) Of Engagement Activity 2008