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Infection and Immunity, January 2009, p. 180-195, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00879-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Direct and Indirect Impairment of Human Dendritic Cell Function by Virulent Francisella tularensis Schu S4{triangledown}

Jennifer C. Chase,1 Jean Celli,2 and Catharine M. Bosio1*

Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,1 Tularemia Pathogenesis Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 598402

Received 16 July 2008/ Returned for modification 1 September 2008/ Accepted 26 October 2008

The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor β, interleukin-10 (IL-10), IL-6, IL-1β, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-{alpha}), and IFN-β throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 µg/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra- and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.

* Corresponding author. Mailing address: Immunity to Pulmonary Pathogens Section, LICP/RML/NIAID/NIH, 303 S. 4th St. Hamilton, MT 59840. Phone: (406) 363-9425. Fax: (406) 363-9380. E-mail: bosioc{at}niaid.nih.gov

{triangledown} Published ahead of print on 3 November 2008.

Editor: S. R. Blanke

Infection and Immunity, January 2009, p. 180-195, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00879-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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