Brain vascular activation is observed in several neurological diseases and often associated with various microbial infections that penetrate into the brain. However, Plasmodium falciparum does not enter the brain but leads to activation of the blood brain barrier (BBB) endothelium and causes cerebral malaria (CM). CM is a clinical syndrome mediated by Plasmodium falciparum infection and associated with a high mortality of up to 30%, particular in children. Acute neurological symptoms and signs include impaired consciousness, coma, delirium, seizures, and increased intracranial hypertension. In African children, persistent neurologic deficits occur after survival of CM episodes. These persistent deficits include, recurrent seizures, loss of developmental milestones, learning disabilities and attention deficit hyperactivity disorder (ADHD). Activation of the BBB endothelium is the result of sequestration of P. falciparum-infected red blood cells (PRBC) to the brain blood vessel endothelium. In contrast to other neuropathogens, PRBC do not cross the BBB into the brain parenchyma. While remaining inside the vascular lumen, PRBC's are still able to elicit acute neuronal dysfunction as named above and the persistent neurological and behavioral deficits afterwards. The molecular and signaling events underlying the neuropathology in CM are unclear. Since the BBB endothelium is located precisely at the interface between PRBC adhesion to the BBB and neuronal dysfunction, we hypothesize that activation of the BBB endothelium plays a crucial role in eliciting central nervous system (CNS) 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 cytokines and chemokines. The release of these factors is directed to both the luminal (apical) side and the brain parenchymal (basal) side. Whereas apical secretions function to alarm the immune system, the basal directed secretions likely contribute to the CNS dysfunction and neurological sequelae in CM. We hypothesize that PRBC-associated changes in the microvascular BBB endothelium result in increased secretion of basal chemokine and growth factors into the brain parenchyma that in turn will increase astroglial activation, impair neuronal functioning and inhibit neuroprogenitor differentiation, therebycontributing to the observed CNS damage and neurologic sequelae in CM. This is a small defined RO3 application that combines the results of in vitro HUMAN BBB activation by a HUMAN pathogen with specific aspects of an in vivo murine model for CM. These studies are important to develop adjunctive therapy that protects against death and cognitive impairment during CM. Moreover, these studies also provide an improved understanding of the BBB and could provide potential new molecular mechanisms that may also function in other neurological diseases.

Public Health Relevance

Cerebrovascular activation is associated with neurologic dysfunction and sequelae and often observed in conjunction with microbial penetration of the brain. Activation of the blood brain barrier (BBB) endothelium is very obvious in cerebral malaria (CM), the most severe complication of Plasmodium infection. Plasmodium infected red blood cells bind to the BBB endothelium and clog up the brain's microvessels, while not invading into the brain;they remain inside the brain blood vessels and activate the blood vessel wall. CM also results in coma and neurologic sequelae such as seizure disorders and ADHD. However, the underlying pathology and how the activation of the blood vessel wall contributes to neurologic sequelae are unclear. In this proposal we intend to study the underlying pathogenesis using in vitro models of the BBB in combination with select use of an in vivo murine model for CM. For future studies we anticipate to validate our results using human tissues.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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Johns Hopkins University
Schools of Medicine
United States
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