HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

PLoS Pathogens

Ebako N. Takem¹  Giorgio Sirugo²  David J. Conway³  Sebastian Weis⁴  Robert Walton⁵  Irene M. Predazzi⁵  Alfred Amambua-Ngwa⁵  Scott M. Williams⁵  Madi Njie⁵  Michael Walther⁵  Augustine Ebonyi⁵  Peter Aka⁵  Sarah Rowland-Jones⁵  Susanne Deininger⁵  Brigitte Walther⁵  Adam De Caul⁶  Aubrey Cunnington⁷ 

[1] Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom;Department of Internal Medicine, Neurology and Dermatology University of Leipzig, Leipzig, Germany;Institute of Health Sciences Education, Barts and the London School of Medicine & Dentistry, Queen Mary University, London, United Kingdom;Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Bonn, Germany;Medical Research Council Laboratories, Fajara, Banjul, Gambia;National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America;Vanderbilt Medical Center, Division of Human Genomics and Center for Human Genetics Research, Nashville, Tennessee, United States of America

关键词: Neutrophils;    Malaria;    Blood;    Heme;    Blood plasma;    Respiratory burst;    Gene expression;    Plasmodium;   

DOI  :  10.1371/journal.ppat.1002579

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.

【 授权许可】

CC BY