Our work in Tanzanian children and Indonesian adults demonstrated impaired production of nitric oxide (NO), impaired mononuclear cell NO synthase 2 (NOS2) expression, and very low levels of the NOS substrate arginine. We concluded that NO and NOS2 are protective against development of severe malaria. NO has antimicrobial effects in vitro against a wide variety of organisms including Plasmodium falciparum, and it can modulate endothelial function (reduction of cell adhesion molecule expression and adherence of parasitized erythrocytes). Arginine can be converted to citrulline and NO by NOS, and to ornithine and urea by arginase. In vivo NO bioavailability can be decreased because of both reduced NO production and hemolysis (hemoglobin and arginase released from erythrocytes can quench NO and consume arginine, respectively). Our studies in Indonesian adults and Tanzanian children confirmed that arginine is low in clinical malaria. We have also shown that adults with moderately severe malaria have endothelial dysfunction as determined by abnormal reactive hyperemia-peripheral arterial tonometry measurements. This reactive hyperemia is primarily dependent on NO. We found that endothelial dysfunction is associated with elevated blood lactate levels, measures of hemolysis, and NO bioavailability. Our studies showed that administration of arginine intravenously to these adults is safe and results in reversion of hypoargininemia, improved endothelial function, and increased exhaled NO. No one has determined the precise cause of hypoargininemia in adults and children who have malaria. Furthermore, no one has evaluated children with malaria for endothelial dysfunction and its relationship to arginine levels and NO production. We hypothesize that hypoargininemia results from a combination of increased arginine degradation and decreased arginine synthesis; that hypoargininemia contributes to the malaria-associated reduced NO bioavailability and endothelial dysfunction; and that hypoargininemia is important in the overall pathophysiology of severe malaria. In addition, we hypothesize that arginine administered in conjunction with parasiticidal antimalarial chemotherapy will be useful in the treatment of severe malaria.
The specific aims are to (1) determine the mechanisms of hypoargininemia in clinical malaria in Tanzanian children; (2) to assess endothelial function in children with malaria with a special emphasis on relationships to arginine levels and NO production; and (3) to perform a dose-ranging study of intravenous arginine administration in hospitalized children with moderately severe malaria. Malaria is the most common cause of hospitalization and death in African children, and there is a high rate of death even in those who receive antimalarial chemotherapy. Our studies will answer important questions regarding the pathophysiology of severe malaria, and the work may lead to new adjunctive treatments for this frequently deadly disease.

Public Health Relevance

Malaria causes more global mortality than any other parasitic disease. Plasmodium falciparum is responsible for severe malaria and the estimated 1.5 to 2.7 million deaths that occur from malaria each year. The majority of these deaths occur in African children less than five years of age. Case fatality rates in severe malaria remain high despite the use of rapidly parasiticidal antimalarial chemotherapy. Adjunctive therapies (treatments added to antimalarial chemotherapy) have not been beneficial. Our earlier studies indicate that arginine (through nitric oxide pathways) may be a useful adjunctive therapy. The studies we propose here will answer important questions relative to the pathophysiology of severe malaria regarding arginine and nitric oxide, and the work may lead to new adjunctive treatments for this frequently deadly disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI041764-11
Application #
7528065
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Rao, Malla R
Project Start
1997-09-30
Project End
2013-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
11
Fiscal Year
2008
Total Cost
$603,941
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Yeo, Tsin W; Florence, Salvatore M; Kalingonji, Ayam R et al. (2017) Decreased Microvascular Function in Tanzanian Children With Severe and Uncomplicated Falciparum Malaria. Open Forum Infect Dis 4:ofx079
Weinberg, J Brice; Volkheimer, Alicia D; Rubach, Matthew P et al. (2016) Monocyte polarization in children with falciparum malaria: relationship to nitric oxide insufficiency and disease severity. Sci Rep 6:29151
Rubach, Matthew P; Mukemba, Jackson; Florence, Salvatore et al. (2015) Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity. PLoS Pathog 11:e1004655
Yeo, Tsin W; Lampah, Daniel A; Kenangalem, Enny et al. (2015) Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation. PLoS Pathog 11:e1004667
Weinberg, Joe Brice; Yeo, Tsin W; Mukemba, Jackson P et al. (2014) Dimethylarginines: endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria. J Infect Dis 210:913-22
Darcy, Christabelle J; Woodberry, Tonia; Davis, Joshua S et al. (2014) Increased plasma arginase activity in human sepsis: association with increased circulating neutrophils. Clin Chem Lab Med 52:573-81
Yeo, Tsin W; Lampah, Daniel A; Kenangalem, Enny et al. (2014) Decreased endothelial nitric oxide bioavailability, impaired microvascular function, and increased tissue oxygen consumption in children with falciparum malaria. J Infect Dis 210:1627-32
Mikita, Kei; Thakur, Kiran; Anstey, Nicholas M et al. (2014) Quantification of Plasmodium falciparum histidine-rich protein-2 in cerebrospinal spinal fluid from cerebral malaria patients. Am J Trop Med Hyg 91:486-92
Wang, Hao; McNeil, Yvette R; Yeo, Tsin W et al. (2013) Simultaneous determination of multiple amino acids in plasma in critical illness by high performance liquid chromatography with ultraviolet and fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 940:53-8
Rubach, Matthew P; Mukemba, Jackson; Florence, Salvatore et al. (2012) Plasma Plasmodium falciparum histidine-rich protein-2 concentrations are associated with malaria severity and mortality in Tanzanian children. PLoS One 7:e35985

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