Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis

PLoS Pathogens

Matthew S. Alkaitis¹  Jessica H. Chertow¹  Aubrey J. Cunnington¹  Hans Ackerman²  Climent Casals-Pascual³  Shamanthi Jayasooriya³  Madi Njie³  Simon Correa³  Michael Walther³  Augustine O. Ebonyi³  Glenn Nardone⁴  Allison K. Ikeda⁵  Joseph Okebe⁶  Oliver Billker⁷  David J. Conway⁸ 

[1] Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America;London School of Hygiene and Tropical Medicine, Bloomsbury, London, United Kingdom;MRC Unit, Fajara, The Gambia;Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington Oxford, United Kingdom;Research Technology Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America;Section of Paediatrics, Imperial College London, London, United Kingdom;Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom;Wellcome Trust Sanger Institute, Hinxton Cambridge, United Kingdom

关键词: Malaria;    Arginine;    Blood plasma;    Nitric oxide;    Plasmodium;    Child health;    Homeostasis;    Malarial parasites;   

DOI  :  10.1371/journal.ppat.1005119

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.

【 授权许可】

CC BY