Influence of genetic variations in TLR4 and TIRAP-Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohortsReportar como inadecuado

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Critical Care

, 14:R103

First Online: 03 June 2010Received: 21 October 2009Revised: 07 April 2010Accepted: 03 June 2010


IntroductionIt has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms SNPs within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer TIRAP-Mal on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.

MethodsThree intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia VAP were included. TLR4 and TIRAP-Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.

ResultsPatients simultaneously carrying polymorphisms in TIRAP-Mal and TLR4 and patients homozygous for the TIRAP-Mal SNP had a significantly higher risk of severe infections after surgery odds ratio OR 5.5; confidence interval CI: 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively. Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP-Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.

ConclusionsCarriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

AbbreviationsCIconfidence interval

DAMPdanger-damage associated molecular patterns

ELISAenzyme-linked immunosorbent assay

GM-CSFgranulocyte macrophage colony-stimulating factor

HMGB-1high-mobility group box-1



IRF3interferon regulatory factor 3

LOSlength of stay



MyD88myeloid differentiation response factor 88

NF-κBnuclear factor-κB

ORodds ratio

PAMPpathogen-associated molecular pattern

PBSphosphate buffered saline

PRRpattern recognition receptor

SDstandard deviation

SIRSsystemic inflammatory response syndrome

SNPsingle nucleotide polymorphism

TIRtoll-interleukin-1 receptor

TIRAPTIR-associated protein

TLRtoll-like receptor

TNF-αtumor necrosis factor-α

Tramtoll-receptor-associated molecule

Triftoll-receptor associated activator of interferon

VAPventilator-associated pneumonia

WTwild type.

Electronic supplementary materialThe online version of this article doi:10.1186-cc9047 contains supplementary material, which is available to authorized users.

Oliver Kumpf, Evangelos J Giamarellos-Bourboulis, Alexander Koch contributed equally to this work.

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Autor: Oliver Kumpf - Evangelos J Giamarellos-Bourboulis - Alexander Koch - Lutz Hamann - Maria Mouktaroudi - Djin-Ye Oh - Eicke 


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