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Inhibition of PKCθ Abrogates CD8+ T Cell-Mediated Neurotoxicity in Murine Cerebral Malaria
Karin Albrecht-Schgör1, Victoria E Stefan2,3, Martina Steinlechner1
1Institute for Cell Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Abstract:
Background: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection that causes devastating brain injury largely through immune-mediated mechanisms. Pathogenic brain-infiltrating CD8+ T cells are key drivers of CM pathology, yet the intracellular signals enabling their harmful autoimmune-like activity remain poorly defined. Here, we identify protein kinase C θ (PKCθ), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKCθ null allele mouse strain on a C57BL/6N background, we demonstrate that PKCθ deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKCθ skews T cell differentiation towards central memory (Tcm) rather than effector memory (Tem) phenotypes, thereby reducing effector differentiation and sequestration of CD8+ T cells in the cerebral microvasculature. This prevents extensive neurovascular damage, preserves neural tissue integrity, and alleviates neurological signs and symptoms. Our findings provide genetic evidence that PKCθ drives CD8+ T cell-mediated brain injury in ECM. Conclusions: These results underscore the potential for repurposing clinically PKCθ inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM.
Insights
Protein kinase C θ (PKCθ) deficiency improves survival in experimental cerebral malaria by reducing harmful CD8+ T cell brain infiltration. This finding suggests PKCθ inhibitors could treat cerebral malaria.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, causing brain injury via immune mechanisms.
- CD8+ T cells are key drivers of CM pathology, but their specific intracellular signaling pathways remain unclear.
- Protein kinase C θ (PKCθ) is identified as a critical intracellular mediator in experimental cerebral malaria (ECM).
Purpose of the Study:
- To investigate the role of PKCθ in the pathogenesis of experimental cerebral malaria (ECM).
- To determine if targeting PKCθ can mitigate brain injury and improve outcomes in ECM.
Main Methods:
- Utilized a PKCθ null allele mouse model on a C57BL/6N background.
- Infected mice with Plasmodium berghei ANKA (PbA) to induce ECM.
- Analyzed parasite burdens, T cell differentiation (Tcm vs. Tem), CD8+ T cell sequestration, neurovascular damage, and neurological symptoms.
Main Results:
- PKCθ deficiency significantly improved survival in PbA-infected mice.
- Loss of PKCθ did not alter parasite burdens in blood or brain.
- PKCθ deficiency skewed CD8+ T cell differentiation towards central memory (Tcm) phenotypes, reducing effector memory (Tem) cells and their cerebral microvasculature sequestration.
- This reduction in T cell sequestration prevented neurovascular damage and neurological symptoms.
Conclusions:
- Genetic evidence shows PKCθ drives CD8+ T cell-mediated brain injury in ECM.
- Targeting PKCθ may offer a host-directed therapeutic strategy for CM.
- Repurposing clinical PKCθ inhibitors could protect against cerebral injury in CM patients.
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