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Infection and Immunity, December 2004, p. 6932-6938, Vol. 72, No. 12
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.12.6932-6938.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nitric Oxide Production and Nitric Oxide Synthase Activity in Malaria-Exposed Papua New Guinean Children and Adults Show Longitudinal Stability and No Association with Parasitemia

Craig S. Boutlis,^1,2* J. Brice Weinberg,³ Joanne Baker,⁴ Moses J. Bockarie,⁵ Charles S. Mgone,^5, Qin Cheng,⁴ and Nicholas M. Anstey^1,2

International Health Program, Division of Infectious Diseases, Menzies School of Health Research Institute of Advanced Studies,¹ Charles Darwin University, Darwin, Northern Territory,² Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Enoggera, Queensland, Australia,⁴ Division of Hematology-Oncology, Department of Medicine, Durham Veterans Administration and Duke University Medical Centers, Durham, North Carolina,³ Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea⁵

Received 5 July 2004/ Returned for modification 23 August 2004/ Accepted 2 September 2004

Individuals in areas of intense malaria transmission exhibit resistance (or tolerance) to levels of parasitemia in their blood that would normally be associated with febrile illness in malaria-naïve subjects. The resulting level of parasitemia associated with illness (the pyrogenic threshold) is highest in childhood and lowest in adulthood. Clinical parallels between malarial and bacterial endotoxin tolerance have led to the supposition that both share common physiological processes, with nitric oxide (NO) proposed as a candidate mediator. The hypotheses that NO mediates tolerance and blood stage parasite killing in vivo were tested by determining its relationship to age and parasitemia cross-sectionally and longitudinally in a population of 195 children and adults from Papua New Guinea encountering intense malaria exposure. Despite pharmacological clearance of asymptomatic parasitemia, NO production and mononuclear cell NO synthase (NOS) activity were remarkably stable within individuals over time, were not influenced by parasitemia, and varied little with age. These results contrast with previous smaller cross-sectional studies. Baseline NO production and NOS activity did not protect against recurrent parasitemia, consistent with previous data suggesting that NO does not have antiparasitic effects against blood stage infection in vivo. The NO indices studied were markedly higher in specimens from study subjects than in samples from Australian controls, and NOS activity was significantly associated with plasma immunoglobulin E levels, consistent with induction of NO by chronic exposure to other infections and/or host genetic factors. These results suggest that NO is unlikely to mediate killing of blood stage parasites in this setting and is unlikely to be the primary mediator in the acquisition or maintenance of malarial tolerance.

Editor: F. C. Fang

Present address: African Malaria Network Trust, Dar es Salaam, Tanzania.