title: T-bet regulates immunity to Francisella tularensis live vaccine strain infection, particularly in lungs.
abstract: Upregulation of the transcription factor T-bet is correlated with the strength of protection against secondary challenge with the live vaccine strain (LVS) of Francisella tularensis. Thus, to determine if this mediator had direct consequences in immunity to LVS, we examined its role in infection. Despite substantial in vivo gamma interferon (IFN-γ) levels, T-bet-knockout (KO) mice infected intradermally (i.d.) or intranasally (i.n.) with LVS succumbed to infection with doses 2 log units less than those required for their wild-type (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 interleukin-17 than WT mice. LVS-vaccinated T-bet-KO mice survived lethal LVS intraperitoneal secondary challenge but not high doses of LVS i.n. challenge, independently of the route of vaccination. Immune T lymphocytes from the spleens of i.d. LVS-vaccinated WT or KO mice controlled intracellular bacterial replication in an in vitro coculture system, but cultures with T-bet-KO splenocyte supernatants contained less IFN-γ and increased amounts of tumor necrosis factor 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.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Melillo
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
authors.forename: Karen L
authors.initials: KL
authors.lastname: Elkins
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005604:Francisella tularensis / Q000276:immunology*; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology; D009573:Nitrites / Q000378:metabolism; D013154:Spleen / Q000382:microbiology; D020825:T-Box Domain Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014406:Tularemia / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D016207:Cytokines; D009573:Nitrites; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma