Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria

Abstract

fThe host immune response plays an important role in the onset and progression of cerebral malaria (CM). The complement system is an essential component of the innate immune response to malaria, and its activation generates the anaphylatoxin C5a. To test the hypothesis that C5a signaling contributes to the pathogenesis of CM, we investigated a causal role for the C5a receptors C5aR and C5L2 in a mouse model of experimental CM (ECM) induced by Plasmodium berghei ANKA infection, and using a case-control design, we examined levels of C5a in plasma samples from Ugandan children presenting with CM or uncomplicated malaria (UM). In the ECM model, C5aR؊/؊ mice displayed significantly improved survival compared to their wild-type (WT) counterparts (P ‫؍‬ 0.004), whereas C5L2 ؊/؊ mice showed no difference in survival from WT mice. Improved survival in C5aR؊/؊ mice was associated with reduced levels of the proinflammatory cytokines tumor necrosis factor (TNF) and gamma interferon (IFN-␥) and the chemokine, monocyte chemoattractant protein 1 (MCP-1) (CCL2). Furthermore, endothelial integrity was enhanced, as demonstrated by increased levels of angiopoietin-1, decreased levels of angiopoietin-2 and soluble ICAM-1, and decreased Evans blue extravasation into brain parenchyma. In the case-control study, the median levels of C5a at presentation were significantly higher in children with CM versus those in children with UM (43.7 versus 22.4 ng/ml; P < 0.001). These findings demonstrate that C5a is dysregulated in human CM and contributes to the pathogenesis of ECM via C5aR-dependent inflammation and endothelial dysfunction.

Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis

“…However, in different animal models, the functions of C5aR and C5L2 are controversial. 17,18 Thus, changes in the expression levels of C5aRs need to be linked with disease status. Under physiological conditions, relatively low levels of C5a may accelerate the priming of neutrophils and monocytes, and also activate endothelial cells, supporting efficient natural immune responses in the case of infections.…”

Complement Factor C5 but Not C3 Contributes Significantly to Hydrosalpinx Development in Mice Infected with Chlamydia muridarum

“…However, only C5aR, and not C5L2, is coupled to G proteins and is usually regarded as the major receptor for C5a to exert the proinflammatory property (24). As a result, efforts at targeting C5aR to attenuate inflammatory damage have been most successful (48,49). We have presented convincing evidence that C5 plays a critical role in chlamydial induction of hydrosalpinx.…”

More than just immune evasion: Hijacking complement by Plasmodium falciparum

“…This is an area of some contention as another study has reported C5aR deletion, but not deletion of the related receptor C5L2, leads to improved survival and reduced levels of inflammatory molecules leading to lower levels of sequestered parasitised erythrocytes and mononuclear cells, easing the cerebral malaria burden (Kim et al, 2014). C5aR deletion mice also displayed enhanced angiogenic stability and enhanced blood brain barrier integrity, loss of which are hallmarks of cerebral malaria, indicating that C5a-C5aR contribute to the loss (Kim et al, 2014). A similar process is seen in experimental lupus, a disease that can cause neurological symptoms (Jacob et al, 2010(Jacob et al, , 2011Kim et al, 2014).…”