Mice deficient in T-bet form inducible NO synthase-positive granulomas that fail to constrain salmonella

Marisol Perez-Toledo, Nonantzin Beristain-Covarrubias, William M. Channel, Jessica R. Hitchcoc, Charlotte N. Cook, Ruth E. Coughla, Saeeda Bobat, Nicholas D. Jone, Kyoko Nakamura, Ewan A. Ros, Amanda E. Rossite, Jessica Rooke, Alicia Garcia-Gimenez, Sian Jossi, Ruby R. Persaud, Edith Marcial-Juarez, Adriana Flores-Langarica, Ian R. Henderso, David R. Wither, Steve P. WatsonAdam F. Cunningham

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

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 STminfected 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.

Original languageEnglish
Pages (from-to)708-719
Number of pages12
JournalJournal of Immunology
Volume205
Issue number3
DOIs
Publication statusPublished - 1 Aug 2020
Externally publishedYes

Fingerprint

Dive into the research topics of 'Mice deficient in T-bet form inducible NO synthase-positive granulomas that fail to constrain salmonella'. Together they form a unique fingerprint.

Cite this