دورية أكاديمية
Salmonella Typhimurium employs spermidine to exert protection against ROS-mediated cytotoxicity and rewires host polyamine metabolism to ameliorate its survival in macrophages.
| العنوان: | Salmonella Typhimurium employs spermidine to exert protection against ROS-mediated cytotoxicity and rewires host polyamine metabolism to ameliorate its survival in macrophages. |
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| المؤلفون: | Nair AV; Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science, Bengaluru, India., Singh A; Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science, Bengaluru, India., Rajmani RS; Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India., Chakravortty D; Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science, Bengaluru, India; Adjunct Faculty, School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, India. Electronic address: dipa@iisc.ac.in. |
| المصدر: | Redox biology [Redox Biol] 2024 Jun; Vol. 72, pp. 103151. Date of Electronic Publication: 2024 Apr 03. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| مواضيع طبية MeSH: | Salmonella typhimurium*/metabolism , Salmonella typhimurium*/drug effects , Spermidine*/metabolism , Macrophages*/microbiology , Macrophages*/metabolism , Macrophages*/drug effects , Reactive Oxygen Species*/metabolism , Bacterial Proteins*/metabolism , Bacterial Proteins*/genetics , NADPH Oxidase 2* , Membrane Proteins*, Animals ; Mice ; Polyamines/metabolism ; Phagocytosis/drug effects ; Salmonella Infections/microbiology ; Salmonella Infections/metabolism ; NADPH Oxidases/metabolism ; NADPH Oxidases/genetics ; Host-Pathogen Interactions ; Spermidine Synthase/metabolism ; Spermidine Synthase/genetics ; Oxidative Stress/drug effects |
| مستخلص: | Salmonella infection entails a cascade of attacks and defence measures. After breaching the intestinal epithelial barrier, Salmonella is phagocytosed by macrophages, where the bacteria encounter multiple stresses, to which it employs relevant countermeasures. Our study shows that, in Salmonella, the polyamine spermidine activates a stress response mechanism by regulating critical antioxidant genes. Salmonella Typhimurium mutants for spermidine transport and synthesis cannot mount an antioxidative response, resulting in high intracellular ROS levels. These mutants are also compromised in their ability to be phagocytosed by macrophages. Furthermore, it regulates a novel enzyme in Salmonella, Glutathionyl-spermidine synthetase (GspSA), which prevents the oxidation of proteins in E. coli. Moreover, the spermidine mutants and the GspSA mutant show significantly reduced survival in the presence of hydrogen peroxide in vitro and reduced organ burden in the mouse model of Salmonella infection. Conversely, in macrophages isolated from gp91phox -/- mice, we observed a rescue in the attenuated fold proliferation previously observed upon infection. We found that Salmonella upregulates polyamine biosynthesis in the host through its effectors from SPI-1 and SPI-2, which addresses the attenuated proliferation observed in spermidine transport mutants. Thus, inhibition of this pathway in the host abrogates the proliferation of Salmonella Typhimurium in macrophages. From a therapeutic perspective, inhibiting host polyamine biosynthesis using an FDA-approved chemopreventive drug, D, L-α-difluoromethylornithine (DFMO), reduces Salmonella colonisation and tissue damage in the mouse model of infection while enhancing the survival of infected mice. Therefore, our work provides a mechanistic insight into the critical role of spermidine in stress resistance of Salmonella. It also reveals a bacterial strategy in modulating host metabolism to promote their intracellular survival and shows the potential of DFMO to curb Salmonella infection. Competing Interests: Declaration of competing interest The authors declare no conflict of interest. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Antioxidative response; D; Glutathionyl-spermidine synthetase; L-α-difluoromethylornithine; Macrophages; Spermidine |
| المشرفين على المادة: | U87FK77H25 (Spermidine) 0 (Reactive Oxygen Species) 0 (Bacterial Proteins) 0 (Polyamines) EC 1.6.3.- (NADPH Oxidases) 0 (SPI-2 protein, Salmonella) EC 2.5.1.16 (Spermidine Synthase) EC 1.6.3.- (Cybb protein, mouse) 0 (Spi1 protein, Salmonella) EC 1.6.3.- (NADPH Oxidase 2) 0 (Membrane Proteins) |
| تواريخ الأحداث: | Date Created: 20240409 Date Completed: 20240505 Latest Revision: 20240505 |
| رمز التحديث: | 20240506 |
| مُعرف محوري في PubMed: | PMC11015157 |
| DOI: | 10.1016/j.redox.2024.103151 |
| PMID: | 38593631 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2213-2317 |
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| DOI: | 10.1016/j.redox.2024.103151 |