A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi).
Intercellular adhesion molecule-1 (ICAM-1) is involved in a range of interactions both within the host and between the host and a number of pathogens. Recently we described a mutation within the coding region of the first N-terminal immunoglobulin-like domain of ICAM-1, present at high frequency within African populations, which increased the risk of cerebral malaria. To understand the mechanism by which such a polymorphism might be maintained despite counter-selection by malaria, we have carried out functional assays using both forms of ICAM-1 as soluble Fc chimeric fusion proteins. ICAM-1Kilifi has reduced avidity for LFA-1 compared with ICAM-1ref and binding to soluble fibrinogen was completely abolished with the Kilifi variant. In Plasmodium falciparum adhesion assays, ITO4-A4u binding to ICAM-1Kilifi was reduced compared with binding to the reference form. These results allow for the possibility of balanced selection between the reference and Kilifi forms of ICAM-1 through modulation of inflammatory responses and indicate the existence of differences within ICAM-1-binding P. falciparum isolates which may be relevant to pathogenesis.
Craig
A
A
Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. agcraig@liverpool.ac.uk
Fernandez-Reyes
D
D
Mesri
M
M
McDowall
A
A
Altieri
D C
DC
Hogg
N
N
Newbold
C
C
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D005340:Fibrinogen / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007630:Kenya; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016779:Malaria, Cerebral / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010963:Plasmodium falciparum / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
D007141:Immunoglobulin Fc Fragments; D016169:Lymphocyte Function-Associated Antigen-1; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen