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Infection and Immunity, June 2006, p. 3262-3270, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.01625-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Plasmodium falciparum-Infected Erythrocytes Increase Intercellular Adhesion Molecule 1 Expression on Brain Endothelium through NF-{kappa}B

Abhai K. Tripathi,1 David J. Sullivan,1 and Monique F. Stins2*

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health,1 Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland2

Received 4 October 2005/ Returned for modification 13 December 2005/ Accepted 2 March 2006

Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-IRBC) in postcapillary brain endothelium is a hallmark of cerebral malaria (CM) pathogenesis. There is a correlation between adherent Pf-IRBC and increased expression of intercellular cell adhesion molecule 1 (ICAM-1), which is also a receptor for Pf-IRBC on human brain microvascular endothelial cells (HBMEC). The underlying mechanism for the increased ICAM-1 expression has not been clearly defined. Therefore, we investigated the mechanisms of ICAM-1 expression on isolated HBMEC after exposure to Pf-IRBC. Ultrastructural characterization of the model confirmed that there was attachment through both Pf-IRBC knobs and HBMEC microvillus protrusions. Pf-IRBC induced a dose- and time-dependent increase in ICAM-1 expression on HBMEC that was specific for human brain endothelium and was not observed with human umbilical vein endothelium. Involvement of both membrane-associated Pf-IRBC proteins and parasite-derived soluble factors with the increase in ICAM-1 expression was demonstrated by surface trypsinization and fractionation. Pf-IRBC exposure induced nuclear translocation of NF-{kappa}B in HBMEC, which was linked to ICAM-1 expression, as shown by use of specific inhibitors of the transcription factor NF-{kappa}B and immunocytochemistry. In addition, inhibition of reactive oxygen species decreased Pf-IRBC-induced ICAM-1 expression on HBMEC. Parasite-induced ICAM-1 expression explains the localization of this molecule on brain endothelium in postmortem CM brain samples. By increasing ICAM-1 expression, Pf-IRBC may increase their sequestration, thereby perpetuating CM.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Pediatrics, School of Medicine, Johns Hopkins University, 720 Rutland Avenue, Ross 1170, Baltimore, MD 21205. Phone: (443) 287-3732. Fax: (410) 614-1315. E-mail: mstins{at}jhmi.edu.

Editor: V. J. DiRita

Infection and Immunity, June 2006, p. 3262-3270, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.01625-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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