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Updated: Apr 16, 2026
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Phosphatidylinositol 3-Kinase γ is required for the development of experimental cerebral malaria
Norinne Lacerda-Queiroz1, Fatima Brant1, David Henrique Rodrigues1
1Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Abstract:
Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.
Insights
Phosphatidylinositol 3-kinase γ (PI3Kγ) plays a key role in experimental cerebral malaria (ECM) pathogenesis. Inhibiting PI3Kγ in mice improved survival and reduced neuroinflammation, suggesting PI3Kγ as a therapeutic target for ECM.
Area of Science:
- Immunology
- Neuroscience
- Pathology
Background:
- Experimental cerebral malaria (ECM) involves significant neuroinflammation, leukocyte infiltration, and blood-brain barrier disruption.
- Phosphatidylinositol 3-kinase γ (PI3Kγ) is a crucial signaling molecule in various cellular processes, including immune responses.
Purpose of the Study:
- To investigate the role of PI3Kγ in the pathogenesis of experimental cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA) infection.
- To evaluate the therapeutic potential of targeting PI3Kγ in ECM.
Main Methods:
- Utilized PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor (AS605240).
- Assessed survival rates, parasitemia, and performed histopathological analyses of brain tissue.
- Quantified microglial activation, T cell cytotoxicity, CD8+ T cell populations, and key signaling molecules (phospho-IkB-α).
Main Results:
- PI3Kγ-/- mice exhibited significantly increased survival rates compared to wild-type mice, despite similar parasite loads.
- Histological examination revealed reduced hemorrhage, leukocyte accumulation, and vascular obstruction in the brains of PI3Kγ-/- mice.
- PI3Kγ deficiency led to decreased microglial activation, T cell cytotoxicity (Granzyme B), and reduced CD8+ T cell infiltration and CD44 expression in the brain.
Conclusions:
- PI3Kγ is critically involved in the neuroinflammatory processes and pathogenesis of experimental cerebral malaria.
- Targeting PI3Kγ demonstrates therapeutic potential, as inhibition significantly improved survival and reduced disease severity in a murine model of ECM.
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