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Role of Complement in Cerebral Malaria

  • Theresa N. Schein
  • Scott R. Barnum
Chapter

Abstract

Studies demonstrate that complement is activated in malaria infections, including cerebral malaria (CM), the most severe form of the disease. Complement-mediated host defense offers little protection against malaria infection. What role then does complement play in malaria infection, particularly CM? Studies demonstrate that C5-deficient mice are highly resistant to experimental CM, the animal model for CM. Using complement-deficient mice, our laboratory surveyed the complement system to address which complement activation pathway(s) and components contribute to ECM development. Surprisingly, C4- and factor B-deficient mice were susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3-deficient mice are susceptible to ECM suggesting that the canonical C5 convertases are not required for ECM development and progression. Mice deficient in the receptors for C3a and C5a are fully susceptible to ECM. These results implicated C5b and the membrane attack complex (MAC) as the drivers of ECM pathogenesis. Indeed, treatment with anti-C9 antibody reduced mortality in ECM. The detection of C5a in the serum of C3-deficient mice suggested cleavage of C5 possibly by the extrinsic protease pathway. Overall, these data indicate that complement-mediated pathogenesis in ECM is terminal pathway dependent.

Keywords

Alternative pathway Anaphylatyoxins Cerebral malaria Classical pathway Convertases Eculizumab Experimental cerebral malaria Extrinsic protease pathway Lectin pathway Membrane attack complex Plasmodium berghei 

Notes

Acknowledgements

The authors acknowledge the support and encouragement of Drs. Julian Rayner and Oliver Billker over the years.

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Authors and Affiliations

  1. 1.CNine Biosolutions, LLCBirminghamUSA

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