Related Experiment Video
Updated: May 21, 2026
Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral
Theresa N Ramos1, Meghan M Darley, Sebastian Weckbach
1Department of Microbiology, University of Alabama, Birmingham, Alabama 35294, USA.
Abstract:
Cerebral malaria (CM) is the most severe manifestation of clinical malaria syndromes and has a high fatality rate especially in the developing world. Recent studies demonstrated that C5(-/-) mice are resistant to experimental CM (ECM) and that protection was due to the inability to form the membrane attack complex. Unexpectedly, we observed that C4(-/-) and factor B(-/-) mice were fully susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3(-/-) mice were also susceptible to ECM, indicating that the canonical C5 convertases are not required for ECM development and progression. Abrogation of ECM by treatment with anti-C9 antibody and detection of C5a in serum of C3(-/-) mice confirmed that C5 activation occurs in ECM independent of C5 convertases. Our data indicate that activation of C5 in ECM likely occurs via coagulation enzymes of the extrinsic protease pathway.
Insights
Complement component C5 activation, not classical pathways, drives severe cerebral malaria (CM). This process likely involves coagulation factors, offering new therapeutic targets for this deadly disease.
Area of Science:
- Immunology
- Pathophysiology
- Complement System
Background:
- Cerebral malaria (CM) is a severe, often fatal complication of malaria.
- The complement system's role in CM pathogenesis is complex and not fully understood.
- Previous studies suggested C5-mediated membrane attack complex formation is crucial for experimental CM (ECM).
Purpose of the Study:
- To investigate the specific pathways of complement activation in experimental cerebral malaria (ECM).
- To determine the role of classical, alternative, and lectin pathways in ECM development.
- To elucidate the mechanism of C5 activation in ECM.
Main Methods:
- Utilized knockout mice deficient in complement components (C3, C4, factor B) and C5.
- Administered anti-C9 antibody to block the membrane attack complex.
- Measured C5a levels in serum of infected mice.
Main Results:
- Mice lacking C4 or factor B were fully susceptible to ECM, ruling out classical/alternative pathway requirement.
- C3-deficient mice were also susceptible, indicating C5 activation is independent of canonical C5 convertases.
- Anti-C9 antibody treatment abrogated ECM, and C5a was detected in C3-deficient mice, confirming C5 activation.
- C5 activation in ECM appears independent of classical C5 convertases.
Conclusions:
- Complement component C5 activation is critical for experimental cerebral malaria pathogenesis.
- ECM development does not require the classical or alternative complement pathways.
- C5 activation in ECM likely occurs via coagulation enzymes from the extrinsic protease pathway, not canonical C5 convertases.
