Complement driven innate immune response to malaria: fuelling severe malarial diseases

Silver, Karlee; Higgins, Sarah J.; McDonald, Chloë R.; Kain, Kevin C.

doi:10.1111/j.1462-5822.2010.01492.x

Cited by 65 publications

(64 citation statements)

References 77 publications

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“…The involvement of complement in Plasmodium infections has been widely reported in malaria literature (10, 112, 113) and extensively reviewed elsewhere (114). Different reports have demonstrated that during ma-laria, complement activation is increased (115,116).…”

Section: The Complement System and Malariamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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The pathogenesis of malaria is complex, generating a broad spectrum of clinical manifestations. One of the major complications and concerns in malaria is anemia, which is responsible for considerable morbidity in the developing world, especially in children and pregnant women. Despite its enormous health importance, the immunological mechanisms involved in malaria-induced anemia remain incompletely understood. Plasmodium vivax, one of the causative agents of human malaria, is known to induce a strong inflammatory response with a robust production of immune effectors, including cytokines and antibodies. Therefore, it is possible that the extent of the immune response not only may facilitate the parasite killing but also may provoke severe illness, including anemia. In this review, we consider potential immune effectors and their possible involvement in generating this clinical outcome during P. vivax infections.

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Section: The Complement System and Malariamentioning

confidence: 99%

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

et al. 2014

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“…However, complement activation is tightly regulated, and the loss of this control can contribute mechanistically to the pathogenesis of multiple conditions, including sepsis, asthma, transplant rejection, and neurodegenerative disorders (18,19,21,22,50). Although previous studies have reported activation of complement via several pathways during malaria infection (23), it has been difficult to determine whether excessive complement activation plays a causal role in the pathogenesis of severe disease in humans. In this study, we present several lines of evidence supporting a causal role for C5a-C5aR signaling in the pathogenesis of CM.…”

Section: Discussionmentioning

confidence: 87%

“…Increased complement activation has been consistently observed in human malaria infections (23). However, in human studies, it has been difficult to establish a causal role for complement activation in the pathogenesis of CM due to the challenges of performing mechanistic studies in human populations.…”

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confidence: 99%

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

Kim

Erdman

et al. 2014

Infect Immun

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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.

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“…4). These studies demonstrate that both the classical and the alternative complement pathways are activated in malaria, whereas the mannose-binding protein pathway is not significantly involved (4).…”

Section: The Canonical C5 Convertases Are Not Required For Ecm Develomentioning

confidence: 99%

The C5 Convertase Is Not Required for Activation of the Terminal Complement Pathway in Murine Experimental Cerebral Malaria

Ramos

Darley

Weckbach

et al. 2012

Journal of Biological Chemistry

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Complement driven innate immune response to malaria: fuelling severe malarial diseases

Cited by 65 publications

References 77 publications

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

Potential Immune Mechanisms Associated with Anemia in Plasmodium vivax Malaria: a Puzzling Question

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

The C5 Convertase Is Not Required for Activation of the Terminal Complement Pathway in Murine Experimental Cerebral Malaria

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