Nuclear factor kappa B-dependent persistence of Salmonella Typhi and Paratyphi in human macrophages.
| Autor: | Stepien TA; Department of Global Health, University of Washington, Seattle, Washington, USA., Singletary LA; Department of Microbiology, University of Washington, Seattle, Washington, USA., Guerra FE; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA., Karlinsey JE; Department of Microbiology, University of Washington, Seattle, Washington, USA., Libby SJ; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA., Jaslow SL; Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA., Gaggioli MR; Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA., Gibbs KD; Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA., Ko DC; Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA., Brehm MA; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA., Greiner DL; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA., Shultz LD; The Jackson Laboratory, Bar Harbor, Maine, USA., Fang FC; Department of Global Health, University of Washington, Seattle, Washington, USA.; Department of Microbiology, University of Washington, Seattle, Washington, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA. |
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| Jazyk: | angličtina |
| Zdroj: | MBio [mBio] 2024 Apr 10; Vol. 15 (4), pp. e0045424. Date of Electronic Publication: 2024 Mar 18. |
| DOI: | 10.1128/mbio.00454-24 |
| Abstrakt: | Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible 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 T Importance: Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Salmonella Typhi and Salmonella Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever Salmonella serovars lack 12 specific virulence factors possessed by nontyphoidal Salmonella serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of Salmonella with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections. Competing Interests: The authors declare no conflict of interest. |
| Databáze: | MEDLINE |
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