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Role of CD40-CVD40L in mouse severe malaria
1Department of Pathology, University of Geneva, 1 rue M. Servet, CMU, 1211 Geneva, Switzerland. pierre.piguet@medecine.unige.ch
Abstract:
We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in +/+ mice, but markedly decreased in CD40-/- or in CD40L-/- mice, as well as in +/+ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected +/+, but not in CD40-/- mice. Thrombocytopenia was less severe in CD40-/- mice than in the +/+ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40-/- or in CD40L-/- mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected +/+ or CD40-/- mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption.
Insights
The CD40-CD40L pathway is crucial for severe malaria mortality in mice. Blocking this interaction significantly reduced deaths by preventing blood-brain barrier damage and macrophage sequestration.
Area of Science:
- Immunology
- Pathology
- Infectious Diseases
Background:
- Severe malaria poses a significant global health threat.
- The CD40-CD40L pathway plays a role in immune responses.
- Understanding molecular mechanisms of malaria pathogenesis is critical.
Purpose of the Study:
- To investigate the role of the CD40-CD40L (CD154) pathway in severe malaria induced by Plasmodium berghei anka infection in mice.
- To determine how CD40-CD40L interaction influences mortality, parasite levels, and organ-specific pathology.
Main Methods:
- Comparison of mortality rates, parasitemia, and blood-brain barrier integrity in wild-type, CD40-deficient, and CD40L-deficient mice infected with Plasmodium berghei anka.
- Assessment of macrophage and parasitized red blood cell sequestration in brain and lung tissues.
- Analysis of CD54 expression and tumor necrosis factor plasma levels.
Main Results:
- Mortality was significantly reduced in CD40- or CD40L-deficient mice compared to wild-type controls (>90% vs. decreased mortality).
- Parasitemia remained similar across groups, indicating CD40-CD40L is not essential for parasite control.
- CD40 deficiency prevented blood-brain barrier breakdown and reduced macrophage sequestration in the brain and lungs.
- Thrombocytopenia was less severe in CD40-deficient mice.
Conclusions:
- The CD40-CD40L interaction is essential for mortality in severe malaria.
- This pathway contributes to critical pathological events including blood-brain barrier disruption, macrophage sequestration, and platelet consumption.
- Targeting the CD40-CD40L pathway may offer a therapeutic strategy for severe malaria.
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