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Updated: Jul 15, 2026
Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Murine cerebral malaria development is independent of toll-like receptor signaling
Dieudonnée Togbe1, Louis Schofield, Georges E Grau
1Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, and University of Orleans, Transgenose Institute, Orleans, France.
Abstract:
Malaria pigment hemozoin was reported to activate the innate immunity by Toll-like receptor (TLR)-9 engagement. However, the role of TLR activation for the development of cerebral malaria (CM), a lethal complication of malaria infection in humans, is unknown. Using Plasmodium berghei ANKA (PbA) infection in mice as a model of CM, we report here that TLR9-deficient mice are not protected from CM. To exclude the role of other members of the TLR family in PbA recognition, we infected mice deficient for single TLR1, -2, -3, -4, -6, -7, or -9 and their adapter proteins MyD88, TIRAP, and TRIF. In contrast to lymphotoxin alpha-deficient mice, which are resistant to CM, all TLR-deficient mice were as sensitive to fatal CM development as wild-type control mice and developed typical microvascular damage with vascular leak and hemorrhage in the brain and lung, together with comparable parasitemia, thrombocytopenia, neutrophilia, and lymphopenia. In conclusion, the present data do not exclude the possibility that malarial molecular motifs may activate the innate immune system. However, TLR-dependent activation of innate immunity is unlikely to contribute significantly to the proinflammatory response to PbA infection and the development of fatal CM.
Insights
Toll-like receptor (TLR) activation does not significantly contribute to cerebral malaria (CM) development. Studies using Plasmodium berghei ANKA infection in mice show that TLR-deficient mice are as susceptible to fatal CM as wild-type controls.
Area of Science:
- Immunology
- Infectious Diseases
- Pathology
Background:
- Malaria pigment hemozoin activates innate immunity via Toll-like receptor (TLR)-9.
- The role of TLR activation in cerebral malaria (CM) pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of TLRs and their adapter proteins in the development of CM using a mouse model.
Main Methods:
- Plasmodium berghei ANKA infection in mice deficient for various TLRs (TLR1, -2, -3, -4, -6, -7, -9) and adapter proteins (MyD88, TIRAP, TRIF).
- Assessment of CM development, including clinical signs, histopathology (vascular leak, hemorrhage), and hematological parameters (parasitemia, thrombocytopenia, neutrophilia, lymphopenia).
Main Results:
- TLR-deficient mice were not protected from fatal CM and exhibited typical CM pathology, similar to wild-type controls.
- Mice deficient in lymphotoxin alpha were resistant to CM, serving as a contrasting control.
- Comparable levels of parasitemia, thrombocytopenia, neutrophilia, and lymphopenia were observed across all groups.
Conclusions:
- TLR-dependent innate immune activation is unlikely to be a major driver of the pro-inflammatory response in Plasmodium berghei ANKA infection.
- The findings suggest that other innate immune pathways, not TLR-dependent ones, may be more critical for CM development.
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