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

被引：78

作者：

Walther, Michael ^{[1
,2
]}

De Caul, Adam ^{[1
]}

Aka, Peter ^{[1
]}

Njie, Madi ^{[1
]}

Amambua-Ngwa, Alfred ^{[1
]}

Walther, Brigitte ^{[1
]}

Predazzi, Irene M. ^{[3
,4
]}

Cunnington, Aubrey ^{[1
,5
]}

Deininger, Susanne ^{[1
,6
]}

Takem, Ebako N. ^{[1
]}

Ebonyi, Augustine ^{[1
]}

Weis, Sebastian ^{[7
]}

Walton, Robert ^{[1
,8
]}

Rowland-Jones, Sarah ^{[1
,9
]}

Sirugo, Giorgio ^{[10
]}

Williams, Scott M. ^{[3
,4
]}

Conway, David J. ^{[1
,5
]}

机构：

[1] MRC Labs, Banjul, Gambia

[2] NIAID, NIH, Rockville, MD USA

[3] Vanderbilt Univ Sch Med, Div Human Genom, Nashville, TN USA

[4] Ctr Human Genet Res, Nashville, TN USA

[5] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London WC1, England

[6] Univ Clin Bonn, Inst Med Microbiol Immunol & Parasitol, Bonn, Germany

[7] Univ Leipzig, Dept Internal Med Neurol & Dermatol, Leipzig, Germany

[8] Queen Mary Univ, Barts & London Sch Med & Dent, Inst Hlth Sci Educ, London, England

[9] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DU, England

[10] Osped San Pietro FBF, Ctr Ric Sci, Ctr Genet, Rome, Italy

来源：

PLOS PATHOGENS | 2012年 / 8卷 / 03期

基金：

英国医学研究理事会;

关键词：

HEME OXYGENASE-1/CARBON MONOXIDE; IRON CHELATION-THERAPY; PLASMODIUM-FALCIPARUM; MICROSATELLITE POLYMORPHISM; CARBON-MONOXIDE; TRANSCRIPTION FACTORS; OXIDATIVE STRESS; CEREBRAL MALARIA; NITRIC-OXIDE; CELL INJURY;

D O I：

10.1371/journal.ppat.1002579

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

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.

引用

页数：17

共 101 条

[21] Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2 [J].