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Infection and Immunity, June 2008, p. 2651-2659, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01412-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Respiratory Francisella tularensis Live Vaccine Strain Infection Induces Th17 Cells and Prostaglandin E₂, Which Inhibits Generation of Gamma Interferon-Positive T Cells

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290

Received 19 October 2007/ Returned for modification 28 November 2007/ Accepted 26 March 2008

Two key routes of Francisella tularensis infection are through the skin and airway. We wished to understand how the route of inoculation influenced the primary acute adaptive immune response. We show that an intranasal inoculation of the F. tularensis live vaccine strain (LVS) with a 1,000-fold-smaller dose than an intradermal dose results in similar growth kinetics and peak bacterial burdens. In spite of similar bacterial burdens, we demonstrate a difference in the quality, magnitude, and kinetics of the primary acute T-cell response depending on the route of inoculation. Further, we show that prostaglandin E₂ secretion in the lung is responsible for the difference in the gamma interferon (IFN-) response. Intradermal inoculation led to a large number of IFN-⁺ T cells 7 days after infection in both the spleen and the lung. In contrast, intranasal inoculation induced a lower number of IFN-⁺ T cells in the spleen and lung but an increased number of Th17 cells in the lung. Intranasal infection also led to a significant increase of prostaglandin E₂ (PGE₂) in the bronchoalveolar lavage fluid. Inhibition of PGE₂ production with indomethacin treatment resulted in increased numbers of IFN-⁺ T cells and decreased bacteremia in the lungs of intranasally inoculated mice. This research illuminates critical differences in acute adaptive immune responses between inhalational and dermal infection with F. tularensis LVS mediated by the innate immune system and PGE₂.

Published ahead of print on 7 April 2008.

Editor: R. P. Morrison