When patients are suffering from the most severe form of malaria, known as cerebral malaria, infected red blood cells are trapped within the microscopic vessels of the brain. This impedes critical oxygen delivery, resulting in coma and often leading to death.

Previous studies by an international team of malaria researchers, including scientists at Duke Medicine, had shown that this condition is also marked by lower production of nitric oxide in the cells lining these micro-vessels. Reversing this deficiency could help prevent malaria-infected red cells from sticking to blood vessel walls and avoid this dire condition.

A follow-up study by these researchers in Tanzania, Indonesia, Australia and the U.S. has shown one reason for poor nitric oxide production. A critical co-factor for an enzyme that produces nitric oxide must be “charged” with potential energy.

This co-factor is called tetrahydrobiopterin (abbreviated BH4). It exists in both energy-rich and energy-drained forms – or like a battery, in a charged and discharged state. In normal cells, the BH4 battery is always poised in the charged state.

Measuring these molecules in children and adults with severe malaria, the researchers found that while the body has plenty of the BH4 co-factor, its form was discharged and therefore unable to supply the energy needed for nitric oxide synthesis.

Why has the so-called battery run down? The answer requires more research, but the investigators speculate that oxygen radicals produced during the inflammation associated with malaria may be draining energy from BH4.

Their results were published in two companion papers in a recent issue of PLoS Pathogens.

The researchers are now trying to determine if there is a way to provide new energy to BH4. Existing therapies for treating vascular disease may hold some promise, the researchers said.

Field research in Dar es Salaam, Tanzania was led by Prof. Esther Mwaikambo of the Hubert Kairuki Memorial University, and in Timika, Papua Indonesia by Dr. Nicholas M. Anstey and Dr. Tsin Yeo of the Menzies Institute for Medical Research, Darwin, Australia.  The U.S. investigators were Dr. J. Brice Weinberg and Dr. Matthew Rubach of Duke University School of Medicine and Durham Veterans Affairs Medical Center and Dr. Donald L. Granger, University of Utah School of Medicine and Salt Lake City Veteran Affairs Medical Center. Weinberg is also a member of the Duke Global Health Institute.

The research was supported by grants from the U.S. National Institutes of Health and the Veterans Affairs Research Service; and by the Australian National Health and Medical Research Council.

Citations:

“Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity”

“Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation”

This article is published in collaboration with Duke Medicine. Publication does not imply endorsement of views by the World Economic Forum.

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Author: Sarah Avery is a Media Relations Officer at Duke Medicine.

Image: Plaster phrenological models of heads, showing different parts of the brain. REUTERS/Chris Helgren.