Donald L. Granger, MD

The pathogenesis of cerebral malaria (CM) is poorly understood. We discovered that Tanzanian children with CM have markedly low plasma levels of arginine (Arg) and markedly elevated phenylalanine (Phe). Arg is needed for synthesis of nitric oxide (NO) by NO synthases (NOS). NO is an important post-synaptic modulator of neurons in the brain. Phe, through its metabolic product, tyrosine (Try), is the substrate for the biogenic amine neurotransmitters (BAN), dopamine, epinephrine and norepinephrine. Enzymes for NO, Tyr and DOPA (precursor of dopamine) synthesis requires the cofactor, tetrahydrobiopterin (BH4). Supply of BH4 during infection is augmented by gamma interferon-induced transcription of GTP cyclohydrolase (GTPCH), the key regulatory enzyme for entrance into this pathway. We have evidence that this response is suppressed in CM. Because of the critical roles of Arg, Phe, NO and BAN in normal brain function, inhibition of synthesis may impact CM pathogenesis. We hypothesize that children with CM are deficient in BH4, that BH4 deficiency causes elevated Phe levels, and that BH4 deficiency causes elevated Phe levels, and that BH4 deficiency in the CNS limits synthesis of BAN leading to brain pathology.

The specific aims are: (1) Determine if children with CM have low systemic levels of BH4; (2) determine if there is CNS deficiency of BH4 and BAN; and (3) whether BH4 deficiency is associated with decreased GTPCH transcription and enzyme activity. In a controlled prospective study, children with CM will donated blood, urine and CSF for measurements of BH4 and BAN metabolites, which will be correlated with clinical status and outcome. Their peripheral blood mononuclear cells will be used to do RT-PCR and immunoblots for GTPCH mRNA and protein.

If the hypotheses are correct, it may be possible to alter CNS disease by administering precursors for BH4 and BAN. Thus the project may lead to rapid translation into trials for management of children with CM.