C5 deficiency and C5a or C5aR blockade protects against cerebral malaria.
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.
Patel
Samir N
SN
Tropical Disease Unit, Department of Medicine, McLaughlin-Rotman Centre for Global Health, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
Berghout
Joanne
J
Lovegrove
Fiona E
FE
Ayi
Kodjo
K
Conroy
Andrea
A
Serghides
Lena
L
Min-oo
Gundula
G
Gowda
D Channe
DC
Sarma
J Vidya
JV
Rittirsch
Daniel
D
Ward
Peter A
PA
Liles
W Conrad
WC
Gros
Philippe
P
Kain
Kevin C
KC
D000818:Animals; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D016779:Malaria, Cerebral / Q000097:blood / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003182:Complement C5; D017931:DNA Primers; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D004247:DNA