Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence
PhoU homologs are one of the determinant factors in the regulation of persister formation and phosphate metabolism in many bacterial species; however, the functions of PhoU homologs exhibit species-specific characteristics. The pathogenesis of Staphylococcus aureus is closely correlated with persist...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00865/full |
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| author | Yongpeng Shang Xiaofei Wang Zhong Chen Zhihui Lyu Zhiwei Lin Jinxin Zheng Yang Wu Qiwen Deng Zhijian Yu Ying Zhang Di Qu |
| author_facet | Yongpeng Shang Xiaofei Wang Zhong Chen Zhihui Lyu Zhiwei Lin Jinxin Zheng Yang Wu Qiwen Deng Zhijian Yu Ying Zhang Di Qu |
| author_sort | Yongpeng Shang |
| collection | DOAJ |
| description | PhoU homologs are one of the determinant factors in the regulation of persister formation and phosphate metabolism in many bacterial species; however, the functions of PhoU homologs exhibit species-specific characteristics. The pathogenesis of Staphylococcus aureus is closely correlated with persister formation and virulence factors. The functions of two PhoU homologs, PhoU1 and PhoU2, in S. aureus are unclear yet. In this study, single- and double-deletion mutants of phoU1 and phoU2 were generated in strain USA500 2395. The ΔphoU1 or ΔphoU2 mutants displayed a change in persister formation and virulence compared to the parent strain; the persisters to vancomycin and levofloxacin were decreased at least 1,000-fold, and the number of intracellular bacteria surviving in the A549 cells for 24 h decreased to 82 or 85%. The α-hemolysin expression and activity were increased in the ΔphoU2 mutants. Transcriptome analysis revealed that 573 or 285 genes were differentially expressed by at least 2.0-fold in the ΔphoU1 or ΔphoU2 mutant vs. the wild type. Genes involved in carbon and pyruvate metabolism were up-regulated, and virulence genes and virulence regulatory genes were down-regulated, including type VII secretion system, serine protease, leukocidin, global regulator (sarA, rot), and the two-component signal transduction system (saeS). Correspondingly, the deletion of the phoU1 or phoU2 resulted in increased levels of intracellular pyruvate and ATP. Deletion of the phoU2, but not the phoU1, resulted in the up-regulation of inorganic phosphate transport genes and increased levels of intracellular inorganic polyphosphate. In conclusion, both PhoU1 and PhoU2 in S. aureus regulate virulence by the down-regulation of multiple virulence factors (type VII secretion system, serine protease, and leucocidin) and the persister generation by hyperactive carbon metabolism accompanied by increasing intracellular ATP. The results in S. aureus are different from what we have previously found in Staphylococcus epidermis, where only PhoU2 regulates biofilm and persister formation. The different functions of PhoU homologs between the two species of Staphylococcus warrant further investigation. |
| first_indexed | 2024-12-20T23:10:51Z |
| format | Article |
| id | doaj.art-310c44c799594804aec278646a4dd3fb |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-20T23:10:51Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-310c44c799594804aec278646a4dd3fb2022-12-21T19:23:44ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-05-011110.3389/fmicb.2020.00865508472Staphylococcus aureus PhoU Homologs Regulate Persister Formation and VirulenceYongpeng Shang0Xiaofei Wang1Zhong Chen2Zhihui Lyu3Zhiwei Lin4Jinxin Zheng5Yang Wu6Qiwen Deng7Zhijian Yu8Ying Zhang9Di Qu10Key Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaKey Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaKey Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaKey Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaDepartment of Infectious Diseases and Shenzhen Key Lab for Endogenous Infection, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, ChinaDepartment of Infectious Diseases and Shenzhen Key Lab for Endogenous Infection, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, ChinaKey Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaDepartment of Infectious Diseases and Shenzhen Key Lab for Endogenous Infection, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, ChinaDepartment of Infectious Diseases and Shenzhen Key Lab for Endogenous Infection, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, ChinaDepartment of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United StatesKey Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaPhoU homologs are one of the determinant factors in the regulation of persister formation and phosphate metabolism in many bacterial species; however, the functions of PhoU homologs exhibit species-specific characteristics. The pathogenesis of Staphylococcus aureus is closely correlated with persister formation and virulence factors. The functions of two PhoU homologs, PhoU1 and PhoU2, in S. aureus are unclear yet. In this study, single- and double-deletion mutants of phoU1 and phoU2 were generated in strain USA500 2395. The ΔphoU1 or ΔphoU2 mutants displayed a change in persister formation and virulence compared to the parent strain; the persisters to vancomycin and levofloxacin were decreased at least 1,000-fold, and the number of intracellular bacteria surviving in the A549 cells for 24 h decreased to 82 or 85%. The α-hemolysin expression and activity were increased in the ΔphoU2 mutants. Transcriptome analysis revealed that 573 or 285 genes were differentially expressed by at least 2.0-fold in the ΔphoU1 or ΔphoU2 mutant vs. the wild type. Genes involved in carbon and pyruvate metabolism were up-regulated, and virulence genes and virulence regulatory genes were down-regulated, including type VII secretion system, serine protease, leukocidin, global regulator (sarA, rot), and the two-component signal transduction system (saeS). Correspondingly, the deletion of the phoU1 or phoU2 resulted in increased levels of intracellular pyruvate and ATP. Deletion of the phoU2, but not the phoU1, resulted in the up-regulation of inorganic phosphate transport genes and increased levels of intracellular inorganic polyphosphate. In conclusion, both PhoU1 and PhoU2 in S. aureus regulate virulence by the down-regulation of multiple virulence factors (type VII secretion system, serine protease, and leucocidin) and the persister generation by hyperactive carbon metabolism accompanied by increasing intracellular ATP. The results in S. aureus are different from what we have previously found in Staphylococcus epidermis, where only PhoU2 regulates biofilm and persister formation. The different functions of PhoU homologs between the two species of Staphylococcus warrant further investigation.https://www.frontiersin.org/article/10.3389/fmicb.2020.00865/fullpersistersPhoU homologStaphylococcus aureusvirulencephosphate metabolismATP |
| spellingShingle | Yongpeng Shang Xiaofei Wang Zhong Chen Zhihui Lyu Zhiwei Lin Jinxin Zheng Yang Wu Qiwen Deng Zhijian Yu Ying Zhang Di Qu Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence Frontiers in Microbiology persisters PhoU homolog Staphylococcus aureus virulence phosphate metabolism ATP |
| title | Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence |
| title_full | Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence |
| title_fullStr | Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence |
| title_full_unstemmed | Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence |
| title_short | Staphylococcus aureus PhoU Homologs Regulate Persister Formation and Virulence |
| title_sort | staphylococcus aureus phou homologs regulate persister formation and virulence |
| topic | persisters PhoU homolog Staphylococcus aureus virulence phosphate metabolism ATP |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00865/full |
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