Cerebral malaria (CM) is a clinical syndrome associated with Plasmodium falciparum infection that is associated with a high mortality of up to 30%, particular in children. Neurological symptoms and signs include impaired consciousness, coma, delirium, seizures, and increased intracranial hypertension. It has recently become apparent that in African children, persistent neurologic deficits, including recurrent seizures and learning disabilities occur after survival of CM episodes. Central to P. falciparum pathophysiology is sequestration of trophozoite and schizont stages of P. falciparum-infected red blood cells (Pf-IRBC) to the brain blood vessel endothelium. Plasmodium differs from other neuropathogens that invade the brain as Pf-IRBC do NOT cross the blood-brain barrier (BBB) into the central nervous system, but are still able to elicit neuronal dysfunction, as observed in P. falciparum CM. It is not known how a parasite, inside an erythrocyte and confined to the blood vessels, is able to induce the neurological signs and symptoms associated with CM. Since the BBB endothelium is located at the interface of these events, we hypothesize that activation of BBB endothelium plays a role in conferring neurological dysfunction. Our published and preliminary data with an in vitro human BBB model show that in CM, the BBB endothelium responds with increased transcription and release of large amounts of cyto- and chemokines towards the brain side and that this that may be responsible and/or contribute significantly to the observed neurological dysfunction in CM. To verify and validate these in vitro findings for the human situation and to assess whether the BBB endothelium would be an appropriate target for adjunctive therapeutic treatment and to prevent neurologic sequelae, it is proposed to assess a specific cyto- chemokine profile in the CSF of CM patients. To accomplish this, we propose a collaboration with the University Hospital of Zambia, Lusaka, Zambia. This is an initial R21 research and capacity building proposal to the NIH Fogarty Program """"""""Brain Disorders in the Developing World: Research across the lifespan"""""""". We intend to set the basis for an extended future collaboration that will focus on the role of chemokines in CM-mediated neurological dysfunction, how this affects a patient's life and development, and how the neurologic sequelae can be prevented in the future.
We propose a research and capacity building collaboration between the University Hospital of Zambia, Lusaka, Zambia and Johns Hopkins University School of Medicine, Baltimore, USA. We aim to verify and validate our findings with a human in vitro cerebral malaria model for the human situation and to assess whether the blood brain barrier endothelium would be an appropriate target for adjunctive therapeutic treatment to prevent neurologic sequelae in CM. We intend to set the basis for an extended future collaboration that will focus on the role of chemokines in CM-mediated neurological dysfunction, how this affects a patient's life and development, and how the neurologic sequelae can be prevented in CM patients