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Infection and Immunity, December 2009, p. 5612-5622, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00618-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection{triangledown}

T. Eoin West,1* Thomas R. Hawn,2 and Shawn J. Skerrett1

Division of Pulmonary and Critical Care Medicine,1 Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington2

Received 1 June 2009/ Returned for modification 2 July 2009/ Accepted 14 September 2009

Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-{kappa}B activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, Box 359640, 325 9th Ave., Seattle, WA 98104. Phone: (206) 897-5271. Fax: (206) 897-5392. E-mail: tewest{at}u.washington.edu

{triangledown} Published ahead of print on 21 September 2009.

Editor: J. L. Flynn

Infection and Immunity, December 2009, p. 5612-5622, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00618-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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