Research & Innovation
Publications
Inhibition of PKCθ Abrogates CD8+ T Cell-Mediated Neurotoxicity in Murine Cerebral Malaria
PMU Author
Victoria E. Stefan
All Authors
Karin Albrecht-Schgor, Victoria E. Stefan, Martina Steinlechner, Dominik Humer, Kerstin Siegmund, Sebastian Peer, Thomas Gruber, Maja Uberegger, Stephanie Zur Nedden, Gabriele Baier-Bitterlich, Peter Lackner, Erich Schmutzhard, Nikolaus Thuille, Victoria Klepsch, Gottfried Baier
Journal association
BIOMEDICINES
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 theta (PKC theta), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKC theta null allele mouse strain on a C57BL/6N background, we demonstrate that PKC theta deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKC theta 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 PKC theta drives CD8(+) T cell-mediated brain injury in ECM. Conclusions: These results underscore the potential for repurposing clinically PKC theta inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM.
Keywords
experimental cerebral malaria (ECM), CD8(+) T cells, cerebral malaria (CM), Drug repurposing, Host-targeted candidate therapy, Immune-mediated brain injury, Neurovascular damage, protein kinase C-theta (PKC theta)