T-bet is required for survival of primary Francisella tularensis LVS infection

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	FDA/CBER	IMMUNO/INFLAM-19

Authors

• A Melillo
• K Elkins

Abstract

Francisella tularensis causes the highly infectious disease tularemia. Identifying correlates of protection is important for vaccine development. Using qualitatively different vaccines, we identified several mediators that correlate with strength of protection against secondary challenge with the Live Vaccine Strain (LVS) of F. tularensis. The T-box transcription factor member T-bet was one such mediator, and was up-regulated in both spleens and lungs of LVS vaccinated mice. Therefore we directly examined T-bet’s role in the immune response against LVS. T-bet-/- mice infected intradermally or intranasally with LVS were highly susceptible compared to WT. The LVS LD50 was 2 logs lower in T-bet-/- mice compared to WT for both routes. Despite reduced IFN-γ, LVS-vaccinated T-bet-/- mice survived lethal LVS secondary challenge. Intramacrophage LVS growth was controlled in co-cultures containing either WT or T-bet-/- immune splenocytes. Co-culture supernatants with T-bet-/- splenocytes exhibited significant decreases in IFN-γ production and increases in TNF-alpha. In contrast, T-bet-/- lung lymphocytes did not control LVS growth. Taken together, we find that T-bet is important in both parenteral and mucosal host resistance to primary LVS infection and thus a useful correlate; however, systemic protection can develop in the absence of T-bet and reduced IFN-γ production.

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