title: Respiratory Francisella tularensis live vaccine strain infection induces Th17 cells and prostaglandin E2, which inhibits generation of gamma interferon-positive T cells.
abstract: 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 E(2) 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 E(2) (PGE(2)) in the bronchoalveolar lavage fluid. Inhibition of PGE(2) 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 PGE(2).
authors.affiliation: University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, NC 27599-7290, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Woolard
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Hensley
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Kawula
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005604:Francisella tularensis / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D014406:Tularemia / Q000276:immunology*
chemical_list: D001428:Bacterial Vaccines; D007371:Interferon-gamma; D015232:Dinoprostone