C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria.
BACKGROUND
Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo.


RESULTS
Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI) enhanced C5a receptor expression (CD88) on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1beta, and IL-10), chemokines (IL-8, MCP-1, MIP1alpha, MIP1beta) and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM.


CONCLUSIONS
These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function.
Conroy
Andrea
A
McLaughlin-Rotman Centre for Global Health, Toronto General Hospital, McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada.
Serghides
Lena
L
Finney
Constance
C
Owino
Simon O
SO
Kumar
Sanjeev
S
Gowda
D Channe
DC
Liles
W Conrad
WC
Moore
Julie M
JM
Kain
Kevin C
KC
D000818:Animals; D002478:Cells, Cultured; D015936:Complement C5a / Q000032:analysis*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007630:Kenya; D008288:Malaria / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology*; D009000:Monocytes / Q000276:immunology / Q000469:parasitology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010920:Placenta / Q000469:parasitology*; D010963:Plasmodium falciparum; D011247:Pregnancy
D015936:Complement C5a