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NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria
Victoria E Stefan1,2, Victoria Klepsch3, Nikolaus Thuille3
1Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
Abstract:
Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8+ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood-brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM.
Insights
NR2F6 deficiency significantly improves survival in experimental cerebral malaria (ECM). This immune checkpoint inhibitor reduces brain pathology and blood-brain barrier damage, offering a potential therapeutic target for CM.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, leading to significant mortality.
- CD8+ T cells play a critical role in CM pathogenesis.
- NR2F6 is an immune checkpoint with a potential role in CM.
Purpose of the Study:
- To investigate the role of NR2F6 in experimental cerebral malaria (ECM).
- To determine if NR2F6 deficiency impacts disease severity and survival.
Main Methods:
- Utilized an experimental mouse model of CM using Plasmodium berghei ANKA (PbA) infection.
- Compared susceptibility between Nr2f6-knock-out and wild-type mice.
- Assessed endotheliopathy, blood-brain barrier (BBB) integrity, parasite sequestration, and T-lymphocyte infiltration in the brain.
Main Results:
- Nr2f6 deficiency conferred a significant survival benefit in mice with ECM.
- Mice lacking NR2F6 exhibited reduced endotheliopathy and BBB damage.
- Decreased parasite sequestration and cytotoxic T-lymphocyte infiltration were observed in the brains of Nr2f6-deficient mice.
Conclusions:
- NR2F6 plays a causal and non-redundant role in the progression of experimental cerebral malaria.
- NR2F6 deficiency confers resistance to ECM.
- Targeting the NR2F6 pathway may offer a therapeutic strategy to protect against CM by maintaining BBB integrity.
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