Salmonella typhimurium Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected Nramp1+/+ Mice and Can Be Reactivated by IFNγ Neutralization

Monack, Denise M.; Bouley, Donna M.; Falkow, Stanley

doi:10.1084/jem.20031319

Cited by 361 publications

(450 citation statements)

References 61 publications

(78 reference statements)

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“…5, A and C) reinforces this conclusion. Thus, the repression of Ag expression below the T cell activation threshold during intracellular growth may functionally contribute to the ability of Salmonella to establish chronic carrier status in mice (53) and humans (54).…”

Section: Discussionmentioning

confidence: 99%

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

Cummings¹,

Barrett²,

Wilkerson³

et al. 2005

The Journal of Immunology

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Salmonella typhimurium, a facultatively intracellular pathogen, regulates expression of virulence factors in response to distinct environments encountered during the course of infection. We tested the hypothesis that the transition from extra- to intracellular environments during Salmonella infection triggers changes in Ag expression that impose both temporal and spatial limitations on the host T cell response. CD4+ T cells recovered from Salmonella immune mice were propagated in vitro using Ag derived from bacteria grown in conditions designed to emulate extra- or intracellular environments in vivo. Extracellular phase bacteria supported a dominant T cell response to the flagellar subunit protein FliC, whereas intracellular phase bacteria were unable to support expansion of FliC-specific T cells from populations known to contain T cells with reactivity to this Ag. This result was attributed to bacterial regulation of FliC expression: transcription and protein levels were repressed in bacteria growing in the spleens of infected mice. Furthermore, Salmonella-infected splenocytes taken directly ex vivo stimulated FliC-specific T cell clones only when intracellular FliC expression was artificially up-regulated. Although it has been suggested that a microanatomical separation of immune T cells and infected APC exists in vivo, we demonstrate that intracellular Salmonella can repress FliC expression below the T cell activation threshold. This potentially provides a mechanism for intracellular Salmonella at systemic sites to avoid detection by Ag-specific T cells primed at intestinal sites early in infection.

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Section: Discussionmentioning

confidence: 99%

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

Cummings¹,

Barrett²,

Wilkerson³

et al. 2005

The Journal of Immunology

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“…Mice that are highly resistant to Salmonella infection can be persistently infected with wild-type S. typhimurium in mesenteric lymph nodes (36). To determine whether Hmp is required for persistent Salmonella infection, we challenged 129Xi/SvJ mice with oral inocula containing equal quantities of wild-type and isogenic hmp mutant bacteria.…”

Section: A Mutation In Hmp But Not the Adhc Norv Or Nrfa Genesmentioning

confidence: 99%

Maintenance of Nitric Oxide and Redox Homeostasis by the Salmonella Flavohemoglobin Hmp

Bang

Liu

Vázquez‐Torres

et al. 2006

Journal of Biological Chemistry

169

191

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Intracellular pathogens must resist the antimicrobial actions of nitric oxide (NO⅐) produced by host cells. To this end pathogens possess several NO⅐-metabolizing enzymes. Here we show that the flavohemoglobin Hmp is the principal enzyme responsible for aerobic NO⅐ metabolism by Salmonella enterica serovar typhimurium. We further show that Hmp is required for Salmonella virulence in mice, in contrast to S-nitrosoglutathione reductase, flavorubredoxin, or cytochrome c nitrite reductase. Abrogation of murine-inducible NO⅐ synthase restores virulence to hmp mutant bacteria. In the presence of nitrosative stress, Hmp-deficient Salmonella exhibits reduced NO⅐ consumption, impaired growth, increased protein S-nitrosylation, and filamentous morphology. However, under aerobic conditions in the absence of nitrosative stress, elevated hmp expression increases S. typhimurium susceptibility to hydrogen peroxide. Both the heme binding and flavoreductase domains are required for resistance to NO⅐, whereas the flavoreductase domain is responsible for iron-dependent susceptibility to oxidative stress. This provides a rationale for the regulation of hmp expression by the transcriptional repressor NsrR in response to both nitrosative stress and intracellular free iron concentration. The Hmp flavohemoglobin plays a central role in the response of Salmonella to nitrosative stress but requires precise regulation to avoid the exacerbation of oxidative stress that can result if electrons are shuttled to extraneous iron.

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“…3,4 Hence, Salmonella have developed species-specific survival strategies that allow for persistent infection, and S. typhimurium infection in mice is a representative model for dissecting the Salmonella-specific immune evasion strategies required for persistent infection. 5,6 T cells play important roles in optimal host defence after primary Salmonella infection in both humans and mice. [7][8][9][10][11] For example, in patients with typhoid fever, the presence of T-cell-mediated immune responses is associated with faster recovery rates and a reduction in diseaserelated sequelae.…”

Section: Introductionmentioning

confidence: 99%

Selective culling of high avidity antigen-specific CD4+ T cells after virulent Salmonella infection

Ertelt¹,

Johanns²,

Mysz

et al. 2011

Immunology

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Summary Typhoid fever is a persistent infection caused by host‐adapted Salmonella strains adept at circumventing immune‐mediated host defences. Given the importance of T cells in protection, the culling of activated CD4+ T cells after primary infection has been proposed as a potential immune evasion strategy used by this pathogen. We demonstrate that the purging of activated antigen‐specific CD4+ T cells after virulent Salmonella infection requires SPI‐2 encoded virulence determinants, and is not restricted only to cells with specificity to Salmonella‐expressed antigens, but extends to CD4+ T cells primed to expand by co‐infection with recombinant Listeria monocytogenes. Unexpectedly, however, the loss of activated CD4+ T cells during Salmonella infection demonstrated using a monoclonal population of adoptively transferred CD4+ T cells was not reproduced among the endogenous repertoire of antigen‐specific CD4+ T cells identified with MHC class II tetramer. Analysis of T‐cell receptor variable segment usage revealed the selective loss and reciprocal enrichment of defined CD4+ T‐cell subsets after Salmonella co‐infection that is associated with the purging of antigen‐specific cells with the highest intensity of tetramer staining. Hence, virulent Salmonella triggers the selective culling of high avidity activated CD4+ T‐cell subsets, which re‐shapes the repertoire of antigen‐specific T cells that persist later after infection.

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Salmonella typhimurium Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected Nramp1+/+ Mice and Can Be Reactivated by IFNγ Neutralization

Cited by 361 publications

References 61 publications

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression

Maintenance of Nitric Oxide and Redox Homeostasis by the Salmonella Flavohemoglobin Hmp

Selective culling of high avidity antigen-specific CD4+ T cells after virulent Salmonella infection

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