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

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Mice deficient in T-bet form inducible NO synthase–positive granulomas that fail to constrain salmonella. / Perez-Toledo, Marisol; Beristain Covarrubias, Noni; Channell, Will; Hitchcock, Jessica; Jones, Charlie; Coughlan, Ruth; Bobat, Saeeda; Jones, Nick; Nakamura, Kyoko; Ross, Ewan; Rossiter, Amanda; Rooke, Jessica; Garcia-Gimenez, Alicia; Jossi, Sian; Persaud, Ruby; Marcial-Juarez, Edith; Flores-Langarica, Adriana; Henderson, Ian; Withers, David; Watson, Steve; Cunningham, Adam.

In: Journal of Immunology, Vol. 205, No. 3, 01.08.2020, p. 708-719.

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Perez-Toledo, Marisol ; Beristain Covarrubias, Noni ; Channell, Will ; Hitchcock, Jessica ; Jones, Charlie ; Coughlan, Ruth ; Bobat, Saeeda ; Jones, Nick ; Nakamura, Kyoko ; Ross, Ewan ; Rossiter, Amanda ; Rooke, Jessica ; Garcia-Gimenez, Alicia ; Jossi, Sian ; Persaud, Ruby ; Marcial-Juarez, Edith ; Flores-Langarica, Adriana ; Henderson, Ian ; Withers, David ; Watson, Steve ; Cunningham, Adam. / Mice deficient in T-bet form inducible NO synthase–positive granulomas that fail to constrain salmonella. In: Journal of Immunology. 2020 ; Vol. 205, No. 3. pp. 708-719.

Bibtex

@article{40157041108d4278a63f6306b36954f8,
title = "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.",
author = "Marisol Perez-Toledo and {Beristain Covarrubias}, Noni and Will Channell and Jessica Hitchcock and Charlie Jones and Ruth Coughlan and Saeeda Bobat and Nick Jones and Kyoko Nakamura and Ewan Ross and Amanda Rossiter and Jessica Rooke and Alicia Garcia-Gimenez and Sian Jossi and Ruby Persaud and Edith Marcial-Juarez and Adriana Flores-Langarica and Ian Henderson and David Withers and Steve Watson and Adam Cunningham",
note = "Funding Information: This work was funded by a grant from the Medical Research Council (MR/N023706/ 1). S.P.W. is a British Heart Foundation chair (CH/03/003). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.",
year = "2020",
month = aug,
day = "1",
doi = "10.4049/jimmunol.2000089",
language = "English",
volume = "205",
pages = "708--719",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

RIS

TY - JOUR

T1 - Mice deficient in T-bet form inducible NO synthase–positive granulomas that fail to constrain salmonella

AU - Perez-Toledo, Marisol

AU - Beristain Covarrubias, Noni

AU - Channell, Will

AU - Hitchcock, Jessica

AU - Jones, Charlie

AU - Coughlan, Ruth

AU - Bobat, Saeeda

AU - Jones, Nick

AU - Nakamura, Kyoko

AU - Ross, Ewan

AU - Rossiter, Amanda

AU - Rooke, Jessica

AU - Garcia-Gimenez, Alicia

AU - Jossi, Sian

AU - Persaud, Ruby

AU - Marcial-Juarez, Edith

AU - Flores-Langarica, Adriana

AU - Henderson, Ian

AU - Withers, David

AU - Watson, Steve

AU - Cunningham, Adam

N1 - Funding Information: This work was funded by a grant from the Medical Research Council (MR/N023706/ 1). S.P.W. is a British Heart Foundation chair (CH/03/003). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85088494185&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.2000089

DO - 10.4049/jimmunol.2000089

M3 - Article

C2 - 32591391

VL - 205

SP - 708

EP - 719

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -