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Cutting edge: the membrane attack complex of complement is required for the development of murine experimental
Theresa N Ramos1, Meghan M Darley, Xianzhen Hu
1Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
Cerebral malaria is the most severe complication of Plasmodium falciparum infection and accounts for a large number of malaria fatalities worldwide. Recent studies demonstrated that C5(-/-) mice are resistant to experimental cerebral malaria (ECM) and suggested that protection was due to loss of C5a-induced inflammation. Surprisingly, we observed that C5aR(-/-) mice were fully susceptible to disease, indicating that C5a is not required for ECM. C3aR(-/-) and C3aR(-/-) × C5aR(-/-) mice were equally susceptible to ECM as were wild-type mice, indicating that neither complement anaphylatoxin receptor is critical for ECM development. In contrast, C9 deposition in the brains of mice with ECM suggested an important role for the terminal complement pathway. Treatment with anti-C9 Ab significantly increased survival time and reduced mortality in ECM. Our data indicate that protection from ECM in C5(-/-) mice is mediated through inhibition of membrane attack complex formation and not through C5a-induced inflammation.
Insights
Protection against experimental cerebral malaria (ECM) in C5-deficient mice is not due to reduced inflammation. Instead, it involves inhibiting the terminal complement pathway and membrane attack complex formation, crucial for ECM development.
Area of Science:
- Immunology
- Infectious Diseases
- Complement System
Background:
- Cerebral malaria (CM) is a severe Plasmodium falciparum complication causing significant mortality.
- Previous studies suggested C5a-mediated inflammation contributes to experimental cerebral malaria (ECM) pathogenesis.
- C5-deficient mice exhibit resistance to ECM, implicating the C5a pathway in disease development.
Purpose of the Study:
- To investigate the role of complement anaphylatoxins (C3a and C5a) and the terminal complement pathway in experimental cerebral malaria (ECM).
- To elucidate the protective mechanisms of C5 deficiency in ECM, challenging the prevailing C5a-inflammation hypothesis.
Main Methods:
- Utilized knockout mice deficient in C5a receptor (C5aR(-/-)) and C3a receptor (C3aR(-/-)), as well as combined deficiencies.
- Administered anti-C9 antibody treatment to wild-type mice during ECM.
- Assessed disease susceptibility, mortality, and survival rates in various mouse models of ECM.
Main Results:
- C5aR(-/-) mice were fully susceptible to ECM, contradicting the protective role of C5a.
- Mice lacking C3aR or both C3aR and C5aR showed susceptibility comparable to wild-type mice.
- C9 deposition was observed in the brains of ECM-affected mice, highlighting the terminal complement pathway's involvement.
- Anti-C9 antibody treatment significantly improved survival and reduced mortality in ECM.
Conclusions:
- The C5a-C5aR axis is not essential for experimental cerebral malaria development.
- Protection in C5-deficient mice against ECM is mediated by the inhibition of membrane attack complex (MAC) formation, not by reduced C5a-induced inflammation.
- The terminal complement pathway, specifically MAC formation, plays a critical role in the pathogenesis of experimental cerebral malaria.
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