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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/24831
Title: Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis)
Authors: W. Joost Wiersinga
Catharina W. Wieland
Mark C. Dessing
Narisara Chantratita
Allen C. Cheng
Direk Limmathurotsakul
Wirongrong Chierakul
Masja Leendertse
Sandrine Florquin
Alex F. De Vos
Nicholas White
Arjen M. Dondorp
Nicholas P. Day
Sharon J. Peacock
Tom Van Der Poll
Academic Medical Centre, University of Amsterdam
Mahidol University
Menzies School of Health Research
University of Oxford
Keywords: Medicine
Issue Date: 1-Jul-2007
Citation: PLoS Medicine. Vol.4, No.7 (2007), 1268-1280
Abstract: Background: Toll-like receptors (TLRs) are essential in host defense against pathogens by virtue of their capacity to detect microbes and initiate the immune response. TLR2 is seen as the most important receptor for gram-positive bacteria, while TLR4 is regarded as the gram-negative TLR. Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia. We aimed to characterize the expression and function of TLRs in septic melioidosis. Methods and Findings: Patient studies: 34 patients with melioidosis demonstrated increased expression of CD14, TLR1, TLR2, and TLR4 on the cell surfaces of monocytes and granulocytes, and increased CD14, TLR1, TLR2, TLR4, LY96 (also known as MD-2), TLR5, and TLR10 mRNA levels in purified monocytes and granulocytes when compared with healthy controls. In vitro experiments: Whole-blood and alveolar macrophages obtained from TLR2 and TLR4 knockout (KO) mice were less responsive to B. pseudomallei in vitro, whereas in the reverse experiment, transfection of HEK293 cells with either TLR2 or TLR4 rendered these cells responsive to this bacterium. In addition, the lipopolysaccharide (LPS) of B. pseudomallei signals through TLR2 and not through TLR4. Mouse studies: Surprisingly, TLR4 KO mice were indistinguishable from wild-type mice with respect to bacterial outgrowth and survival in experimentally induced melioidosis. In contrast, TLR2 KO mice displayed a markedly improved host defenses as reflected by a strong survival advantage together with decreased bacterial loads, reduced lung inflammation, and less distant-organ injury. Conclusions: Patients with melioidosis displayed an up-regulation of multiple TLRs in peripheral blood monocytes and granulocytes. Although both TLR2 and TLR4 contribute to cellular responsiveness to B. pseudomallei in vitro, TLR2 detects the LPS of B. pseudomallei, and only TLR2 impacts on the immune response of the intact host in vivo. Inhibition of TLR2 may be a novel treatment strategy in melioidosis. © 2007 Wiersinga et al.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=34547607225&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/24831
ISSN: 15491676
15491277
Appears in Collections:Scopus 2006-2010

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