: Malaria causes more mortality globally than any other parasitic disease, yet a full understanding of protective immune responses and disease patho-physiology is lacking, and effective treatments for severe malaria are limited. Nitric oxide (NO) has antimicrobial effects in vitro against a wide variety of organisms including Plasmodium falciparum. In addition, NO has anti-disease effects against malaria in vivo. Our detailed field studies (in both African children and Indonesian adults) have shown a highly significant inverse association between disease severity and blood mononuclear cell (PBMC) inducible NO synthase (NOS2) expression and systemic NO production. We have discovered novel polymorphisms in NOS2 and related genes that are significantly associated with NO production and resistance to severe malaria. This proposal is designed to continue our NIH-funded work to clarify the role of NO in clinical immunity to malaria and protection from severe malaria. We will extend our current case-control studies in Tanzania and Irian Jaya to confirm the association of our newly identified polymorphisms with disease manifestations and severity, and we will undertake functional studies of these polymorphisms in healthy subjects and those with malaria. In longitudinal studies of patients with both severe and uncomplicated malaria, we will investigate the relationship between the ability of host PBMC to express NOS2 and the susceptibility to severe malaria.
Our aims are (1) to characterize the association of novel NOS2 and related genetic polymorphisms with malaria disease severity in two separate populations; (2) to determine the functional significance of these malaria-related NOS2 polymorphisms (both in vitro and in vivo); and (3) in longitudinal studies, to determine whether PBMC NOS2 expression and activity relate directly to an individual's susceptibility to severe malaria. Accomplishing our stated goals will be very significant in adding to the understanding of host resistance to malaria infection and resistance to severe malaria. Also, information learned from this work will likely be applicable to other infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
2R21AI041764-06
Application #
6547991
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rao, Malla R
Project Start
1997-09-30
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2002
Total Cost
$490,014
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
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
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
Randall, Louise M; Kenangalem, Enny; Lampah, Daniel A et al. (2010) Age-related susceptibility to severe malaria associated with galectin-2 in highland Papuans. J Infect Dis 202:117-24

Showing the most recent 10 out of 14 publications