NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria.

Cerebral malaria (CM) is the severe progression of an infection with , causing detrimental damage to brain tissue and is the most frequent cause of 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 ANKA () infection to compare the relative susceptibility of -knock-out and wild-type C57BL6/N mice. As a remarkable result, 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.