Nair, AV and Singh, A and Rajmani, RS and Chakravortty, D (2024) Salmonella Typhimurium employs spermidine to exert protection against ROS-mediated cytotoxicity and rewires host polyamine metabolism to ameliorate its survival in macrophages. In: Redox Biology, 72 .
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Abstract
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. © 2024 The Authors
| Item Type: | Journal Article |
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| Publication: | Redox Biology |
| Publisher: | Elsevier B.V. |
| Additional Information: | The copyright for this article belongs to authors. |
| Keywords: | eflornithine; glutathionyl spermidine synthetase; hydrogen peroxide; polyamine; reactive oxygen metabolite; spermidine; synthetase; unclassified drug, animal cell; animal experiment; antioxidant activity; antioxidant gene; Article; bacterial colonization; bacterial gene; bacterial survival; bacterium isolation; bacterium mutant; biosynthesis; cell level; controlled study; cytotoxicity; Escherichia coli; host; host bacterium interaction; in vitro study; macrophage; metabolic regulation; metabolism; mouse; mouse model; nonhuman; phagocytosis; physiological stress; polyamine biosynthesis; Salmonella enterica serovar Typhimurium; salmonellosis; survival; tissue injury; upregulation |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology |
| Date Deposited: | 08 Jul 2024 11:35 |
| Last Modified: | 08 Jul 2024 11:35 |
| URI: | http://eprints.iisc.ac.in/id/eprint/84753 |
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