1. Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella .
- Author
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Perez-Toledo M, Beristain-Covarrubias N, Channell WM, Hitchcock JR, Cook CN, Coughlan RE, Bobat S, Jones ND, Nakamura K, Ross EA, Rossiter AE, Rooke J, Garcia-Gimenez A, Jossi S, Persaud RR, Marcial-Juarez E, Flores-Langarica A, Henderson IR, Withers DR, Watson SP, and Cunningham AF
- Subjects
- Animals, Granuloma genetics, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-17 genetics, Interleukin-17 immunology, Mice, Mice, Knockout, Nitric Oxide Synthase Type II genetics, Salmonella Infections genetics, Salmonella typhimurium genetics, T-Box Domain Proteins immunology, Granuloma immunology, Nitric Oxide Synthase Type II immunology, Salmonella Infections immunology, Salmonella typhimurium immunology, T-Box Domain Proteins deficiency, Th1 Cells immunology
- 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., (Copyright © 2020 The Authors.)- Published
- 2020
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