[HTML][HTML] Mice deficient in T-bet form inducible NO synthase–positive granulomas that fail to constrain salmonella
M Perez-Toledo, N Beristain-Covarrubias… - The Journal of …, 2020 - journals.aai.org
M Perez-Toledo, N Beristain-Covarrubias, WM Channell, JR Hitchcock, CN Cook…
The Journal of Immunology, 2020•journals.aai.orgClearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-
γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ−/− mice
succumb rapidly to STm infections, T-bet−/− 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 STm-infected IFN-γ−/− and T-bet−/− mice. In IFN-γ−/− mice, there is deficient
granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination …
γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ−/− mice
succumb rapidly to STm infections, T-bet−/− 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 STm-infected IFN-γ−/− and T-bet−/− mice. In IFN-γ−/− mice, there is deficient
granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination …
Abstract
Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ−/− mice succumb rapidly to STm infections, T-bet−/− 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 STm-infected IFN-γ−/− and T-bet−/− mice. In IFN-γ−/− 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-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet−/− mice induce significant levels of IFN-γ− after challenge. Moreover, T-bet−/− 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-bet−/− 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-bet−/− mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ–dependent iNOS+ granulomas and prevent dissemination.
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