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Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis).
PLoS Med. 2007 Jul 31; 4(7):e248.PM

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.

Authors+Show Affiliations

Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17676990

Citation

Wiersinga, W Joost, et al. "Toll-like Receptor 2 Impairs Host Defense in Gram-negative Sepsis Caused By Burkholderia Pseudomallei (Melioidosis)." PLoS Medicine, vol. 4, no. 7, 2007, pp. e248.
Wiersinga WJ, Wieland CW, Dessing MC, et al. Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis). PLoS Med. 2007;4(7):e248.
Wiersinga, W. J., Wieland, C. W., Dessing, M. C., Chantratita, N., Cheng, A. C., Limmathurotsakul, D., Chierakul, W., Leendertse, M., Florquin, S., de Vos, A. F., White, N., Dondorp, A. M., Day, N. P., Peacock, S. J., & van der Poll, T. (2007). Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis). PLoS Medicine, 4(7), e248.
Wiersinga WJ, et al. Toll-like Receptor 2 Impairs Host Defense in Gram-negative Sepsis Caused By Burkholderia Pseudomallei (Melioidosis). PLoS Med. 2007 Jul 31;4(7):e248. PubMed PMID: 17676990.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis). AU - Wiersinga,W Joost, AU - Wieland,Catharina W, AU - Dessing,Mark C, AU - Chantratita,Narisara, AU - Cheng,Allen C, AU - Limmathurotsakul,Direk, AU - Chierakul,Wirongrong, AU - Leendertse,Masja, AU - Florquin,Sandrine, AU - de Vos,Alex F, AU - White,Nicholas, AU - Dondorp,Arjen M, AU - Day,Nicholas P, AU - Peacock,Sharon J, AU - van der Poll,Tom, PY - 2006/10/04/received PY - 2007/06/19/accepted PY - 2007/8/7/pubmed PY - 2007/12/11/medline PY - 2007/8/7/entrez SP - e248 EP - e248 JF - PLoS medicine JO - PLoS Med VL - 4 IS - 7 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/17676990/Toll_like_receptor_2_impairs_host_defense_in_gram_negative_sepsis_caused_by_Burkholderia_pseudomallei__Melioidosis__ L2 - https://dx.plos.org/10.1371/journal.pmed.0040248 DB - PRIME DP - Unbound Medicine ER -