Scientific Publications by FDA Staff

Infect Immun 2014 Apr;82(4):1477-90

T-bet regulates immunity to Francisella tularensis live vaccine strain infection, particularly in lungs.

Melillo AA, Foreman O, Bosio CM, Elkins KL

Upregulation of the transcription factor T-bet is correlated with strength of protection against secondary challenge with the Live Vaccine Strain (LVS) of Francisella tularensis, which causes the highly infectious disease tularemia. Thus, to determine if this mediator had direct consequences in immunity to LVS, we examined its role in infection. Despite substantial in vivo IFN-gamma levels, T-bet knockout (KO) mice infected intradermally (i.d.) or intranasally (i.n.) with LVS succumbed to infection with doses 2 logs less than WT counterparts, and exhibited significantly increased bacterial burdens in the lung and spleen. Lungs of LVS-infected T-bet KO mice contained fewer lymphocytes, and more neutrophils and IL-17, compared to WT mice. LVS-vaccinated T-bet KO mice survived lethal LVS intraperitoneal secondary challenge, but not high doses of LVS i.n., independent of route of vaccination. Immune T-lymphocytes from spleens of i.d. LVS-vaccinated WT or KO mice controlled intracellular bacterial replication in an in vitro co-culture system, but cultures with T-bet KO splenocytes supernatants contained less IFN-gamma and increased TNF-alpha. In contrast, immune T-bet KO lung lymphocytes were greatly impaired in controlling intramacrophage growth of LVS; this functional defect is the likely mechanism underpinning the lack of respiratory protection. Taken together, T-bet is important in host resistance to primary LVS infection, and i.n. secondary challenge. Thus, T-bet represents a true, useful correlate for immunity to LVS.