The Journal of Experimental Medicine
ThymUS '08
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Published online April 21, 2008
doi:10.1084/jem.20072248
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Patel et al.
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ARTICLE

 C5 deficiency and C5a or C5aR blockade protects against cerebral malaria

Samir N. Patel1,2,3, Joanne Berghout5, Fiona E. Lovegrove1,2,3, Kodjo Ayi1,2, Andrea Conroy1,2,4, Lena Serghides2, Gundula Min-oo5, D. Channe Gowda6, J. Vidya Sarma7, Daniel Rittirsch7, Peter A. Ward7, W. Conrad Liles1,2,3, Philippe Gros5, and Kevin C. Kain1,2,3,4

1 Tropical Disease Unit, Department of Medicine, McLaughlin-Rotman Centre for Global Health, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada
2 McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada
3 Institute of Medical Sciences and 4 Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
5 Department of Biochemistry and Centre for the Study of Host Resistance, McGill University, Montreal, Quebec H3G 1Y6, Canada
6 Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033
7 Department of Pathology, University of Michigan, Ann Arbor, MI 48109

CORRESPONDENCE Kevin C. Kain: kevin.kain{at}uhn.on.ca

Experimental infection of mice with Plasmodium berghei ANKA (PbA) provides a powerful model to define genetic determinants that regulate the development of cerebral malaria (CM). Based on the hypothesis that excessive activation of the complement system may confer susceptibility to CM, we investigated the role of C5/C5a in the development of CM. We show a spectrum of susceptibility to PbA in a panel of inbred mice; all CM-susceptible mice examined were found to be C5 sufficient, whereas all C5-deficient strains were resistant to CM. Transfer of the C5-defective allele from an A/J (CM resistant) onto a C57BL/6 (CM-susceptible) genetic background in a congenic strain conferred increased resistance to CM; conversely, transfer of the C5-sufficient allele from the C57BL/6 onto the A/J background recapitulated the CM-susceptible phenotype. The role of C5 was further explored in B10.D2 mice, which are identical for all loci other than C5. C5-deficient B10.D2 mice were protected from CM, whereas C5-sufficient B10.D2 mice were susceptible. Antibody blockade of C5a or C5a receptor (C5aR) rescued susceptible mice from CM. In vitro studies showed that C5a-potentiated cytokine secretion induced by the malaria product P. falciparum glycosylphosphatidylinositol and C5aR blockade abrogated these amplified responses. These data provide evidence implicating C5/C5a in the pathogenesis of CM.

Abbreviations used: CM, cerebral malaria; PbA, Plasmodium berghei ANKA; PfGPI, P. falciparum glycosylphosphatidylinositol; TLR, Toll-like receptor.

P. Gros and K.C. Kain contributed equally to this work.


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