Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy
ABSTRACT Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for Staphylococcus aureus survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitr...
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| Language: | English |
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American Society for Microbiology
2025-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.04006-24 |
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| author | Nadira Nurxat Qichen Wang Na Zhao Yanan Guo Xilong Zhang Yanan Wang Ying Jian Hua Wang Shengbing Yang Min Li Qian Liu |
| author_facet | Nadira Nurxat Qichen Wang Na Zhao Yanan Guo Xilong Zhang Yanan Wang Ying Jian Hua Wang Shengbing Yang Min Li Qian Liu |
| author_sort | Nadira Nurxat |
| collection | DOAJ |
| description | ABSTRACT Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for Staphylococcus aureus survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitrate reductase (NR) is affected by molybdopterin biosynthesis protein A (MoeA), which is essential for molybdenum cofactor synthesis in S. aureus. During the infection, the production of endogenous NO promotes S. aureus survival inside macrophages by initiating cellular autophagy. Mechanistically, bacterial endogenous NO can modify the host regulatory protein thioredoxin vis S-nitrosylation, subsequently triggering the phosphorylation of the JNK-Bcl-2 pathway and promoting the initiation of autophagy through the release of Beclin1. Moreover, we confirmed the critical role of MoeA in bacterial survival in vivo by using bloodstream infection, pneumonia, and skin abscess model on both wild-type and autophagy-deficient mice. Interestingly, we observed the significantly increased production of NO and activation of cellular autophagy of sequence type (ST)5 compared with ST239, suggesting that the initiation of autophagy is involved in the clone shift of S. aureus. Our data offered new insights on the role of bacterial endogenous NO in regulating the host signal pathway during infection inside host cells.IMPORTANCEUnderstanding the mechanism underlying Staphylococcus aureus pathogenesis is essential for developing innovative strategies for the prevention and treatment of infection. In this study, we underscore the critical role of molybdopterin biosynthesis protein A and nitric oxide (NO) in inducing autophagy during S. aureus survival within macrophage and in vivo infection. We demonstrate that host regulatory protein can be modified by bacterial metabolites, which may influence cellular processes. Furthermore, our findings indicated that increased endogenous NO production may contribute to the stable prevalence of S. aureus ST5 in the healthcare-associated environment. These findings highlight the significance of bacterial metabolism in modulating the host immune system, thereby facilitating S. aureus survival and persistence. |
| format | Article |
| id | doaj-art-582d1601adaf404a8a5b5d65c5be7572 |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-582d1601adaf404a8a5b5d65c5be75722025-08-20T02:16:46ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.04006-24Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagyNadira Nurxat0Qichen Wang1Na Zhao2Yanan Guo3Xilong Zhang4Yanan Wang5Ying Jian6Hua Wang7Shengbing Yang8Min Li9Qian Liu10Department of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaCollege of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaShanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Laboratory Medicine, Shanghai Jiao Tong University, Shanghai, ChinaABSTRACT Endogenous nitric oxide (NO) is a small molecule that has been demonstrated to affect the physiology and survival of bacteria. The role of endogenous NO for Staphylococcus aureus survival inside host cells remains unclear. Here, we show that the production of endogenous NO by bacterial nitrate reductase (NR) is affected by molybdopterin biosynthesis protein A (MoeA), which is essential for molybdenum cofactor synthesis in S. aureus. During the infection, the production of endogenous NO promotes S. aureus survival inside macrophages by initiating cellular autophagy. Mechanistically, bacterial endogenous NO can modify the host regulatory protein thioredoxin vis S-nitrosylation, subsequently triggering the phosphorylation of the JNK-Bcl-2 pathway and promoting the initiation of autophagy through the release of Beclin1. Moreover, we confirmed the critical role of MoeA in bacterial survival in vivo by using bloodstream infection, pneumonia, and skin abscess model on both wild-type and autophagy-deficient mice. Interestingly, we observed the significantly increased production of NO and activation of cellular autophagy of sequence type (ST)5 compared with ST239, suggesting that the initiation of autophagy is involved in the clone shift of S. aureus. Our data offered new insights on the role of bacterial endogenous NO in regulating the host signal pathway during infection inside host cells.IMPORTANCEUnderstanding the mechanism underlying Staphylococcus aureus pathogenesis is essential for developing innovative strategies for the prevention and treatment of infection. In this study, we underscore the critical role of molybdopterin biosynthesis protein A and nitric oxide (NO) in inducing autophagy during S. aureus survival within macrophage and in vivo infection. We demonstrate that host regulatory protein can be modified by bacterial metabolites, which may influence cellular processes. Furthermore, our findings indicated that increased endogenous NO production may contribute to the stable prevalence of S. aureus ST5 in the healthcare-associated environment. These findings highlight the significance of bacterial metabolism in modulating the host immune system, thereby facilitating S. aureus survival and persistence.https://journals.asm.org/doi/10.1128/mbio.04006-24nitric oxidemetabolismStaphylococcus aureusvirulenceautophagy |
| spellingShingle | Nadira Nurxat Qichen Wang Na Zhao Yanan Guo Xilong Zhang Yanan Wang Ying Jian Hua Wang Shengbing Yang Min Li Qian Liu Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy mBio nitric oxide metabolism Staphylococcus aureus virulence autophagy |
| title | Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy |
| title_full | Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy |
| title_fullStr | Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy |
| title_full_unstemmed | Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy |
| title_short | Endogenous nitric oxide promotes Staphylococcus aureus virulence by activating autophagy |
| title_sort | endogenous nitric oxide promotes staphylococcus aureus virulence by activating autophagy |
| topic | nitric oxide metabolism Staphylococcus aureus virulence autophagy |
| url | https://journals.asm.org/doi/10.1128/mbio.04006-24 |
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