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Human Molecular Genetics, 2000, Vol. 9, No. 4 525-530
© 2000 Oxford University Press

A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi)

Alister Craig+, Delmiro Fernandez-Reyes, Mehdi Mesri1, Alison McDowall2, Dario C. Altieri1, Nancy Hogg2 and Christopher Newbold

Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK, 1Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, PO Box 9812, New Haven, CT 06536-0812, USA and 2Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund Laboratories, PO Box123, Lincoln’s Inn Fields, London WC2A 3PX, UK

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.

+ To whom correspondence should be addressed. Tel: +44 151 708 9393; Fax: +44 151 708 9007; Email: agcraig@liverpool.ac.uk


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