Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.

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.

• Authors: Marisol Perez-Toledo, Nonantzin Beristain-Covarrubias, William M Channell, Jessica R Hitchcock, Charlotte N Cook, Ruth E Coughlan, Saeeda Bobat, Nicholas D Jones, Kyoko Nakamura, Ewan A Ross, Amanda E Rossiter, Jessica Rooke, Alicia Garcia-Gimenez, Sian Jossi, Ruby R Persaud, Edith Marcial-Juarez, Adriana Flores-Langarica, Ian R Henderson, David R Withers, Steve P Watson, Adam F Cunningham
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 205 Issue 3 Pg. 708-719 (08 01 2020) ISSN: 1550-6606 [Electronic] United States
• PMID: 32591391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors.

Chemical References

• IFNG protein, mouse
• Il17a protein, mouse
• Interleukin-17
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Interferon-gamma
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Granuloma (genetics, immunology)
• Interferon-gamma (genetics, immunology)
• Interleukin-17 (genetics, immunology)
• Mice
• Mice, Knockout
• Nitric Oxide Synthase Type II (genetics, immunology)
• Salmonella Infections (genetics, immunology)
• Salmonella typhimurium (genetics, immunology)
• T-Box Domain Proteins (deficiency, immunology)
• Th1 Cells (immunology)