Document Type
Article
Publication Date
4-10-2024
Original Citation
Stepien T,
Singletary L,
Guerra F,
Karlinsey J,
Libby S,
Jaslow S,
Gaggioli M,
Gibbs K,
Ko D,
Brehm M,
Greiner D,
Shultz LD,
Fang F.
Nuclear factor kappa B-dependent persistence of mBio. 2024;15(4):e0045424
Keywords
JMG, Humans, Animals, Mice, Salmonella typhi, Typhoid Fever, NF-kappa B, Macrophages, Salmonella
JAX Source
mBio. 2024;15(4):e0045424
ISSN
2150-7511
PMID
38497655
DOI
https://doi.org/10.1128/mbio.00454-24
Grant
HHS | National Institutes of Health (NIH) OD0426640 Michael A. Brehm Dale L. Greiner Leonard D. Shultz HHS | National Institutes of Health (NIH) AI132963 Michael A. Brehm Leonard D. Shultz HHS | National Institutes of Health (NIH) OD018259 Leonard D. Shultz HHS | National Institutes of Health (NIH) CA034196 Leonard D. Shultz
Abstract
Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsi ble for the divergent clinical manifestations of nontyphoidal and enteric fever Salmonella infections have remained elusive. Here, we show that S. Typhi and S. Paratyphi A can persist within human macrophages, whereas S. Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on Salmonella pathogenicity island 2 (SPI2). S. Typhi and S. Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of S. Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired TH1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow S. Typhi and S. Paratyphi A to cause chronic infections.
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