A2AR as candidate pathological driver of cerebral malaria

Cerebral malaria (CM) is the most severe complication of malaria. Currently, there is no adjuvant treatment option for CM. In a mouse model of experimental cerebral malaria (ECM), we observed for the first time that the adenosine 2a receptor (A2AR) plays a crucial role in the pathogenesis of cerebral malaria. Indeed, mice are protected from malaria-induced brain damage when either the A2AR gene is knocked out in the germline or a systemic A2AR receptor antagonist is administered. On a mechanistic level, we were able to identify A2AR as an immune checkpoint. In ECM diseases, the A2AR signaling pathway controls CD8+ T cell effector function. Therefore, the inactivation of A2AR can be used to counteract immune- mediated inflammation and tissue damage in ECM. Therefore, the aim of the FWF grant is the further preclinical validation of our hypothesis. At the same time, the molecular and cellular mechanisms will be the subject of detailed investigation. Since the discovery of the role of the A2AR pathway in ECM pathogenesis was made by our colleague Karin Albrecht-Schgör in our laboratory, we expect that this work will lead to a much better understanding of the adaptive immune response in malaria in general and ECM pathogenesis in particular. Our research may thus provide the basis for developing new therapeutic options for CM in humans using A2AR antagonists, which are already clinically approved for other indications. Principal Investigator (PI): Prof. Gottfried Baier Co-Principal Investigator (Co-PI): Prof. Erich Schmutzhard, emeritus Co-Principal Investigator (Co-PI): Ass.-Prof. Nikolaus Thuille