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Infection and Immunity, August 2007, p. 4127-4137, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.01868-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 2-Mediated Signaling Requirements for Francisella tularensis Live Vaccine Strain Infection of Murine Macrophages{triangledown}

Leah E. Cole,1 Kari Ann Shirey,1 Eileen Barry,2 Araceli Santiago,2 Prasad Rallabhandi,1 Karen L. Elkins,3 Adam C. Puche,4 Suzanne M. Michalek,5 and Stefanie N. Vogel1*

Department of Microbiology and Immunology,1 Center for Vaccine Development,2 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201,4 Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Allergenic, and Parasitic Products, CBER, Food and Drug Administration, Bethesda, Maryland 20852,3 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352945

Received 27 November 2006/ Returned for modification 5 January 2007/ Accepted 10 May 2007

Francisella tularensis, an aerobic, non-spore-forming, gram-negative coccobacillus, is the causative agent of tularemia. We reported previously that F. tularensis live vaccine strain (LVS) elicited strong, dose-dependent NF-{kappa}B reporter activity in Toll-like receptor 2 (TLR2)-expressing HEK293T cells and proinflammatory gene expression in primary murine macrophages. Herein, we report that F. tularensis LVS-induced murine macrophage proinflammatory cytokine gene and protein expression are overwhelmingly TLR2 dependent, as evidenced by the abrogated responses of TLR2–/– macrophages. F. tularensis LVS infection also increased expression of TLR2 both in vitro, in mouse macrophages, and in vivo, in livers from F. tularensis LVS-infected mice. Colocalization of intracellular F. tularensis LVS, TLR2, and MyD88 was visualized by confocal microscopy. Signaling was abrogated if the F. tularensis LVS organisms were heat or formalin killed or treated with chloramphenicol, indicating that the TLR2 agonist activity is dependent on new bacterial protein synthesis. F. tularensis LVS replicates in macrophages; however, bacterial replication was not required for TLR2 signaling because LVS{Delta}guaA, an F. tularensis LVS guanine auxotroph that fails to replicate in the absence of exogenous guanine, activated NF-{kappa}B in TLR2-transfected HEK293T cells and induced cytokine expression in wild-type macrophages comparably to wild-type F. tularensis LVS. Collectively, these data indicate that the primary macrophage response to F. tularensis LVS is overwhelmingly TLR2 dependent, requires de novo bacterial protein synthesis, and is independent of intracellular F. tularensis replication.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Maryland, Baltimore, 660 West Redwood Street, Room 324, Baltimore, MD 21201. Phone: (410) 706-4838. Fax: (410) 706-8607. E-mail: svogel{at}som.umaryland.edu

{triangledown} Published ahead of print on 21 May 2007.

Editor: J. L. Flynn

Infection and Immunity, August 2007, p. 4127-4137, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.01868-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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