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Role of ICAM-1 (CD54) in the development of murine cerebral malaria
N Favre1, C Da Laperousaz, B Ryffel
1Department of Medical Parasitology, Swiss Tropical Institute, Postfach, CH-4002 Basel, Switzerland.
Abstract:
In susceptible mouse strains, infection of mice with Plasmodium berghei ANKA (PbA) results in a lethal complication, cerebral malaria. Cerebral malaria is due to the immune response induced by the parasite, which results in an increased production of TNF, known to increase the expression of adhesion molecules on the endothelia. To investigate the role of the adhesion molecule ICAM-1 (CD54), we infected wild-type (+/+) and ICAM-1-deficient (-/-) mice with PbA. While +/+ mice died 6-8 days after infection, -/- mice survived > 15 days. Parasitaemia was similar in +/+ and -/- mice. Serum TNF concentration was increased by the infection and was significantly higher in infected +/+ than in -/- mice. However, TNF mRNA levels in spleen, lungs, and brain were elevated in both infected +/+ and -/- mice. For IFN-gamma, serum levels were similar in both groups. A breakdown of the blood-brain barrier was evident in infected +/+ mice only. Interestingly, thrombocytopenia was profound in infected +/+, but practically absent in -/- mice. Moreover, macrophage sequestration was evident in brain venules and lung capillaries of +/+ mice and was significantly less important in the alveolar capillaries of infected -/- mice. In contrast, neutrophil sequestration in the lung was similar in both +/+ and -/- mice. Sequestration of parasitized red blood cells was significantly greater in the alveolar capillaries from +/+ than -/- mice. These results indicate that while the immune response is similar in both +/+ and ICAM-1(-/-) mice, the absence of mortality in ICAM(-/-) mice correlates with a decrease of macrophage and parasitized RBC trapping and a less severe thrombocytopenia.
Insights
Intercellular Adhesion Molecule-1 (ICAM-1) deficiency protects mice from lethal cerebral malaria by reducing parasite sequestration and macrophage trapping, despite similar immune responses. This highlights ICAM-1
Area of Science:
- Immunology
- Pathology
- Parasitology
Background:
- Plasmodium berghei ANKA (PbA) infection causes lethal cerebral malaria in susceptible mice.
- Cerebral malaria pathogenesis involves parasite-induced immune responses, including TNF production and increased endothelial adhesion molecule expression.
Purpose of the Study:
- To investigate the role of the adhesion molecule ICAM-1 (CD54) in the development of cerebral malaria.
- To compare PbA infection outcomes in wild-type and ICAM-1-deficient mice.
Main Methods:
- Infection of wild-type (+/+) and ICAM-1-deficient (-/-) mice with PbA.
- Monitoring of survival, parasitemia, serum TNF and IFN-gamma levels.
- Analysis of blood-brain barrier integrity, thrombocytopenia, and immune cell/parasitized RBC sequestration in various organs.
Main Results:
- ICAM-1-deficient mice survived significantly longer than wild-type mice.
- Parasitemia and IFN-gamma levels were similar between groups; serum TNF was higher in wild-type mice.
- Reduced breakdown of the blood-brain barrier, less severe thrombocytopenia, and decreased sequestration of macrophages and parasitized red blood cells in ICAM-1-deficient mice.
Conclusions:
- ICAM-1 plays a critical role in PbA-induced cerebral malaria pathogenesis.
- Absence of ICAM-1 protects mice by mitigating vascular sequestration and associated pathologies.
- Targeting ICAM-1 may offer a therapeutic strategy against cerebral malaria.