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Infection and Immunity, July 2007, p. 3571-3580, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.01644-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evaluation of the Role of LcrV-Toll-Like Receptor 2-Mediated Immunomodulation in the Virulence of Yersinia pestis{triangledown}

Kimberly Pouliot,1 Ning Pan,1 Shixia Wang,2 Shan Lu,2 Egil Lien,2 and Jon D. Goguen1*

Department of Molecular Genetics and Microbiology,1 Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 016552

Received 11 October 2006/ Returned for modification 26 November 2006/ Accepted 30 March 2007

Pathogenic members of the Yersinia genus require the translocator protein LcrV for proper function of the type III secretion apparatus, which is crucial for virulence. LcrV has also been reported to play an independent immunosuppressive role via the induction of interleukin-10 (IL-10) through stimulation of Toll-like receptor 2 (TLR2). To investigate the LcrV-TLR2 interaction in vitro, His-tagged recombinant LcrV (rLcrV) from Yersinia pestis was cloned and expressed in Escherichia coli and purified through Ni-nitrilotriacetic acid column chromatography. High concentrations (5 µg/ml) of rLcrV stimulated TLR2 in vitro. Fractionation of rLcrV preparations via gel filtration revealed that only a minor component consisting of high-molecular-weight multimers or aggregates has TLR2 stimulating activity. Dimer and tetramer forms of rLcrV, which constitute the bulk of the material, do not have this activity. To investigate the potential role of LcrV/TLR2 in plague pathogenesis, we infected wild-type and TLR2–/– mice with virulent Y. pestis. No discernible difference between the two mouse strains in severity of disease or kinetics of survival after subcutaneous challenge was observed. IL-6, tumor necrosis factor, and IL-10 levels from spleen homogenates; bacterial load; and the extent of inflammation observed in organs from mice infected intravenously were also indistinguishable in both mouse strains. Taken together, our data indicate that the most abundant molecular species of Y. pestis LcrV do not efficiently activate TLR2-signaling and that TLR2-mediated immunomodulation is unlikely to play a significant role in plague.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: (508) 856-2490. Fax: (508) 856-3355. E-mail: jon.goguen{at}umassmed.edu

{triangledown} Published ahead of print on 16 April 2007.

Editor: J. B. Bliska

Infection and Immunity, July 2007, p. 3571-3580, Vol. 75, No. 7
0019-9567/07/$08.00+0     doi:10.1128/IAI.01644-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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