NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria
Cerebral malaria (CM) is the severe progression of an infection with <i>Plasmodium falciparum</i>, causing detrimental damage to brain tissue and is the most frequent cause of <i>Plasmodium falciparum</i> mortality. The critical role of brain-infiltrating CD8<sup>+</...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/15/1162 |
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| Summary: | Cerebral malaria (CM) is the severe progression of an infection with <i>Plasmodium falciparum</i>, causing detrimental damage to brain tissue and is the most frequent cause of <i>Plasmodium falciparum</i> mortality. The critical role of brain-infiltrating CD8<sup>+</sup> 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 <i>Plasmodium berghei</i> ANKA (<i>PbA</i>) infection to compare the relative susceptibility of <i>Nr2f6</i>-knock-out and wild-type C57BL6/N mice. As a remarkable result, <i>Nr2f6</i> 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. |
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| ISSN: | 2073-4409 |