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Infection and Immunity, March 2009, p. 1238-1245, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01078-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Live Borrelia burgdorferi Spirochetes Elicit Inflammatory Mediators from Human Monocytes via the Toll-Like Receptor Signaling Pathway{triangledown}

Vida A. Dennis,1* Saurabh Dixit,1 Shannon M. O'Brien,1 Xavier Alvarez,2 Bapi Pahar,2 and Mario T. Philipp1*

Divisions of Bacteriology and Parasitology,1 Comparative Pathology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana2

Received 29 August 2008/ Returned for modification 9 November 2008/ Accepted 1 January 2009

We investigated the mechanisms that lead to the production of proinflammatory mediators by human monocytes when these cells are exposed in vitro to live Borrelia burgdorferi spirochetes. We first focused on myeloid differentiation primary response protein 88 (MyD88), an adapter molecule that is essential in the Toll-like receptor (TLR) pathway. Real-time PCR, flow cytometry, and confocal microscopy experiments revealed that MyD88 was maximally expressed in THP-1 cells after 24-h stimulation of these cells with live B. burgdorferi. Silencing of the MYD88 gene by using small interfering RNA resulted in 24%, 35%, and 84% down-modulation of the production of tumor necrosis factor alpha (TNF-{alpha}), interleukin-8 (IL-8), and IL-6, respectively, in THP-1 cells stimulated with live B. burgdorferi. Specific silencing of the TLR1, TLR2, or TLR5 gene by RNA interference further revealed that silencing of the TLR1 and TLR2 genes alone or combined, but not the TLR5 gene, caused a downregulation of IL-6, IL-8, and TNF-{alpha} in live B. burgdorferi-stimulated THP-1 cells. Overall, similar results were obtained for THP-1 cells stimulated with purified lipoproteins. Our results indicate that the TLR pathway mediates, at least in part, the release of inflammatory mediators in human monocytes stimulated with live B. burgdorferi spirochetes and furthermore suggest that the TLR-dependent interaction between these cells and live spirochetes is mediated by spirochetal lipoproteins but not by flagellin.

* Corresponding author. Mailing address for Vida A. Dennis: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, 18703 Three Rivers Rd., Covington, LA 70433. Phone: (985) 871-6221. Fax: (985) 871-6390. E-mail: vida{at}tulane.edu. E-mail for Mario T. Philipp: Philipp{at}tulane.edu

{triangledown} Published ahead of print on 12 January 2009.

Editor: J. F. Urban, Jr.

Infection and Immunity, March 2009, p. 1238-1245, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.01078-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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