Cerebral malaria is associated with decreased production of nitric oxide and decreased levels of its precursor, L-arginine. Abnormal amino acid metabolism may thus be an important factor in malaria pathogenesis. We sought to determine if other amino acid abnormalities are associated with disease severity in falciparum malaria. Subjects were enrolled in Dar es Salaam, Tanzania (children) (n ‫؍‬ 126), and Papua, Indonesia (adults) (n ‫؍‬ 156), in two separate studies. Plasma samples were collected from subjects with WHO-defined cerebral malaria (children), all forms of severe malaria (adults), and uncomplicated malaria (children and adults). Healthy children and adults without fever or illness served as controls. Plasma amino acids were measured using reverse-phase high-performance liquid chromatography with fluorescence detection. Several plasma amino acids were significantly lower in the clinical malaria groups than in healthy controls. Despite the differences, phenylalanine was the only amino acid with mean levels outside the normal range ( The coma of cerebral malaria (CM) is frequently accompanied by seizures and abnormalities of muscle tone and posture (23). The mechanisms of these neurological complications are unclear; however, cerebral ischemia is unlikely to be the sole explanation, as survivors are usually neurologically intact (17). Altered amino acid metabolism in response to malaria infection may contribute to disease severity. Circulating amino acids serve primarily as substrates for protein synthesis, metabolic energy (oxidation through the carboxylic acid cycle), or gluconeogenesis and ketogenesis. Importantly, certain amino acids are also substrates for neurochemical mediators, which can be increased by inflammatory stimuli. For example, gamma interferon increases metabolism of tryptophan through the kynurenine pathway, resulting in the production of the excitatory mediators quinolinic acid, kynurenic acid, and picolinic acid. These have been investigated as possible contributors to the neurologic dysfunction of CM (15).We have previously shown that plasma levels of the nitric oxide (NO) precursor L-arginine were significantly reduced in African children with CM relative to levels in healthy controls (HC) and those with uncomplicated malaria (UM) (14). In addition, case fatality rates from CM were independently associated with the degree of hypoargininemia. These results paralleled previous work demonstrating similarly reduced systemic levels of NO metabolites and NO synthase expression in blood mononuclear cells from children with CM relative to those of patients with UM and controls (1). In extending our amino acid analysis from those previous studies, we discovered abnormalities in plasma phenylalanine levels in children with malaria. Additionally, we measured phenylalanine levels in plasma collected from Indonesian adults with severe malaria (SM) and UM. Here, we describe our findings and discuss how they may relate to the neurological complications of CM. MATERIALS AND METHODSSubjects. Plasm...

Individuals living in regions of intense malaria transmission exhibit natural immunity that allows them to be without fever and other symptoms for most of the time despite frequent parasitization. Although this tolerance of parasitemia appears to be more effective in children than in adults (as evidenced by lower parasitemia fever thresholds with age), adults do exhibit a degree of tolerance but the mechanism(s) underlying this are unclear. Asymptomatic malaria-exposed children have higher levels of nitric oxide (NO) than children with severe disease, and NO has been proposed as a mediator of malarial tolerance. However, the ability of highly malaria-exposed asymptomatic adults to generate high-level basal NO is unknown, as is the relationship between NO and malaria tolerance in adults. The relationship between NO and malaria parasitemia was therefore determined in asymptomatic adults from Papua, Indonesia. Adults with Plasmodium falciparum parasitemia had markedly increased basal systemic NO production relative to aparasitemic Papuan controls, who in turn produced more NO than healthy controls from a region without malaria. Immunoglobulin E levels were universally elevated in malaria-exposed Papuan subjects, suggesting that the prevalence of intestinal parasitosis may be high and that nonmalarial infection may also contribute to high basal NO production. Basal peripheral blood mononuclear cell (PBMC) NO synthase activity was elevated in Papuans but poorly correlated with systemic NO production, suggesting that NO production in this setting arises not only from PBMCs but also from other tissue and cellular sources. NO production was associated with and may contribute to malaria tolerance in Papuan adults.The natural history of malaria in regions where it is endemic is characterized by long periods of asymptomatic parasitemia punctuated by episodic clinical attacks that decrease in frequency with age (40, 57). Although the immune processes preventing symptoms such as fever in chronically parasitized individuals are poorly understood, this aspect of immunity (malarial tolerance) is thought to be most efficient in childhood and then declines with age (18,41,70). This is because the threshold of parasitemia associated with fever appears to be age dependent and higher in children than adults from geographically diverse regions where malaria is endemic (56, 65). Nitric oxide (NO) has been proposed as the mediator of tolerance in populations in regions where malaria is endemic (15) on the basis that NO production in asymptomatic malariaexposed children exceeds that of children with severe malaria (1, 5) and that parallels exist between the malaria tolerant state and endotoxin tolerance (72). Indeed, in 1965 it was shown that cross-tolerance to bacterial lipopolysaccharide could be induced by experimentally infecting prisoners with Plasmodium vivax (61); this finding is in accord with present molecular models of tolerance (21). Downregulation of the endogenous pyrogen tumor necrosis factor alpha (TNF-␣) and upregulation...