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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{triangledown}

Matthew D. Woolard, Lucinda L. Hensley, Thomas H. Kawula, and Jeffrey A. Frelinger*

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-{gamma}) response. Intradermal inoculation led to a large number of IFN-{gamma}+ T cells 7 days after infection in both the spleen and the lung. In contrast, intranasal inoculation induced a lower number of IFN-{gamma}+ 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-{gamma}+ 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.

* Corresponding author. Mailing address: University of North Carolina, Department of Microbiology and Immunology, CB# 7290 Jones, Chapel Hill, NC 27599-7290. Phone: (919) 966-2599. Fax: (919) 962-8103. E-mail: jfrelin{at}med.unc.edu

{triangledown} Published ahead of print on 7 April 2008.

Editor: R. P. Morrison

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.



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