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Infection and Immunity, June 2003, p. 3155-3164, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3155-3164.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Optimal Tumor Necrosis Factor Induction by Plasmodium falciparum Requires the Highly Localized Release of Parasite Products

Kieran P. O'Dea* and Geoffrey Pasvol

Wellcome Centre for Clinical Tropical Medicine, Department of Infection and Tropical Medicine, Imperial College London, The Lister Unit, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom

Received 22 July 2002/ Returned for modification 10 October 2002/ Accepted 17 March 2003

Overproduction of tumor necrosis factor (TNF) has been linked with the pathogenesis of Plasmodium falciparum malaria. Here, we examined why the high levels of TNF-inducing activity associated with P. falciparum-parasitized erythrocytes (PE) appear to be lost after cell lysis. Static coculture of PE and peripheral blood mononuclear cells (PBMC), with or without separation by porous membranes, demonstrated that rupture of live PE in the presence of responder cells was required for optimal TNF induction. Although the insoluble fraction of lysed PE was found to partially inhibit TNF responses, supernatants prepared from large numbers of lysed PE still contained only low levels of TNF-inducing activity, which showed no evidence of instability. A dramatic reduction in TNF levels resulted when noncytoadherent PE lines were maintained under low-cell-proximity conditions by suspension coculture. This reduction was much less marked with PE capable of adhering to PBMC, despite the fact that cytoadherent and noncytoadherent parasite lines induced comparable levels of TNF in high-cell-proximity, static coculture. These results suggest that rupture of PE in a highly localized setting, facilitated by either static coculture or the more biologically relevant phenomenon of cytoadherence to PBMC, can result in considerable enhancement of the P. falciparum-induced TNF response.

* Corresponding author. Mailing address: Department of Anaesthetics and Intensive Care, Imperial College Faculty of Medicine, Chelsea and Westminster Hospital, 369 Fulham Rd., London SW10 9NH, United Kingdom. Phone: 44 20 8237 5111. Fax: 44 20 8237 5109. E-mail: k.odea{at}ic.ac.uk.

Editor: J. M. Mansfield

Infection and Immunity, June 2003, p. 3155-3164, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3155-3164.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Clark, I. A., Alleva, L. M., Mills, A. C., Cowden, W. B. (2004). Pathogenesis of Malaria and Clinically Similar Conditions. Clin. Microbiol. Rev. 17: 509-539 [Abstract] [Full Text]  


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