Nitric Oxide Synthase Substrate Availability in Severe Malaria

Friday, November 08, 2013 — Poster Session III
10:00 a.m. – 12:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIAID	MICROBIO-1

Authors

M.S. Alkaitis
H. Wang
H.C. Ackerman

Abstract

Patients with severe P. falciparum malaria exhibit profound depletion of L-arginine, the substrate for nitric oxide synthesis. L-arginine is a key intermediate in the urea cycle, in which the cyclical interconversion of arginine, ornithine and citrulline drives detoxification of ammonia waste and synthesis of urea. Previous studies have suggested that blood stage malaria infection releases and/or activates parasite- and host-derived arginase enzymes, which convert arginine to ornithine and urea. All other variables remaining constant, accelerated arginase activity would predict an increase in the ratio of ornithine to arginine. However, we demonstrate that all three major urea cycle intermediates (arginine, ornithine, and citrulline) are depleted to similar degrees in mice and human patients with severe malaria, yielding no change in the ornithine/arginine ratio. We also rule out changes in daily food intake as a possible cause of arginine depletion in malaria-infected mice. Based on these data, we hypothesize that arginine depletion can best be explained by increased utilization of one or more urea cycle intermediates for alternate metabolic purposes. We propose to test this hypothesis by using mass spectrometry to determine the rates of appearance and conversion of 13C-, 15N- and deuterium-labeled metabolic tracers infused into healthy and malaria-infected mice.