학술논문
Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.
Document Type
Article
Author
Perez-Toledo, Marisol; Beristain-Covarrubias, Nonantzin; Channell, William M.; Hitchcock, Jessica R.; Cook, Charlotte N.; Coughlan, Ruth E.; Bobat, Saeeda; Jones, Nicholas D.; Kyoko Nakamura; Ross, Ewan A.; Rossiter, Amanda E.; Rooke, Jessica; Garcia-Gimenez, Alicia; Jossi, Sian; Persaud, Ruby R.; Marcial-Juarez, Edith; Flores-Langarica, Adriana; Henderson, Ian R.; Withers, David R.; Watson, Steve P.
Source
Subject
*TH1 cells
*NITRIC-oxide synthases
*GRANULOMA
*SALMONELLA
*MICE
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Language
ISSN
0022-1767
Abstract
Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-g and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-g2/2 mice succumb rapidly to STm infections, T-bet2/2 mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STminfected IFN-g2/2 and T-bet2/2 mice. In IFN-g2/2 mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-g reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-g. T-bet2/2 mice induce significant levels of IFN-g2 after challenge. Moreover, T-bet2/2 mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet2/2 mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet2/2 mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-g-dependent iNOS+ granulomas and prevent dissemination. [ABSTRACT FROM AUTHOR]