Deletion of OTUD7B in astrocytes protects against cerebral malaria by inhibiting microvesicle-induced TRAF3/TRAF6-mediated neuroinflammation

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Damage of the blood-brain barrier (BBB) and endothelial dysfunction are established drivers of the disease pathology, however, whether astrocytes, a major constituent of the BBB, influence the disease outcome remains unclear. Using the murine model of experimental cerebral malaria (ECM), we show that astrocytes decisively regulate the outcome of ECM and the deubiquitinating enzyme OTUD7B in astrocytes fosters the disease. Mice lacking astrocytic OTUD7B showed reduced brain pathology and were protected from ECM compared with wildtype littermate controls. Transcriptomic profiling of ex vivo-isolated astrocytes revealed reduced proinflammatory chemokines and cytokines in the absence of OTUD7B. Plasmodium infection-associated microvesicles triggered a pro-inflammatory response in astrocytes, which was dependent on OTUD7B. Mechanistically, OTUD7B cleaved K48-linked ubiquitin chains from TRAF3 and TRAF6 upon stimulation with microvesicles or activation of TLR3/TLR9 by plasmodial nucleic acids. The OTUD7B-dependent TRAF3 and TRAF6 stabilization led to sustained NF-{kappa}B and p38 MAP kinase signaling and CXCL10 expression. Therapeutic silencing of CNS Otud7b or Cxcl10 expression after disease onset protected mice from ECM, identifying the cerebral OTUD7B-Cxcl10 axis as an attractive therapeutic target.