Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin
ABSTRACT The increasingly serious problem of bacterial drug resistance has led to the development of antivirulence agents. The Salmonella enterica serovar Typhimurium Salmonella pathogenicity island (SPI)-encoded type III secretion system (T3SS) and its effector proteins are important virulence fact...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02949-22 |
| _version_ | 1811194680939905024 |
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| author | Yunjia Shi Zeyu Sun Yang Liu Jingyan Shu Yong Zhang Qianghua Lv Jianfeng Wang Xuming Deng Hongtao Liu Jiazhang Qiu |
| author_facet | Yunjia Shi Zeyu Sun Yang Liu Jingyan Shu Yong Zhang Qianghua Lv Jianfeng Wang Xuming Deng Hongtao Liu Jiazhang Qiu |
| author_sort | Yunjia Shi |
| collection | DOAJ |
| description | ABSTRACT The increasingly serious problem of bacterial drug resistance has led to the development of antivirulence agents. The Salmonella enterica serovar Typhimurium Salmonella pathogenicity island (SPI)-encoded type III secretion system (T3SS) and its effector proteins are important virulence factors for S. Typhimurium invasion and replication in host cells and for antivirulence drug screening. Fraxetin is isolated from Fraxinus spp. Extensive studies have reported its multiple pharmacological activities. However, it remains to be elucidated whether fraxetin affects the function of the S. Typhimurium T3SS. In this study, the anti-infection mechanism of fraxetin on S. Typhimurium and its T3SS was investigated. Fraxetin inhibited the S. Typhimurium invasion of HeLa cells without affecting the growth of bacteria in vitro. Further findings on the mechanism showed that fraxetin had an inhibitory effect on the S. Typhimurium T3SS by inhibiting the transcription of the pathogenesis-related SPI-1 transcriptional activator genes hilD, hilC, and rtsA. Animal experiments showed that fraxetin treatment protected mice against S. Typhimurium infection. Collectively, we provide the first demonstration that fraxetin may serve as an effective T3SS inhibitor for the development of treatments for Salmonella infection. IMPORTANCE The increasingly serious problem of bacterial antibiotic resistance limits the clinical application of antibiotics, which increases the need for the development of antivirulence agents. The type III secretion system (T3SS) plays a critical role in host cell invasion and pathogenesis of Salmonella and becomes a popular target for antivirulence agents screening. Our study found, for the first time, that fraxetin inhibited S. Typhimurium invasion by inhibiting the transcription of genes in a feed-forward regulatory loop. Further in vivo testing showed that fraxetin decreased bacterial burdens in the spleen and liver of S. Typhimurium-infected mice and improved survival outcomes in an in vivo mouse model of S. Typhimurium infection. Collectively, these results demonstrate that fraxetin inhibits S. Typhimurium infection by targeting the T3SS and may serve as a potential agent for the treatment of S. Typhimurium infection. |
| first_indexed | 2024-04-12T00:30:46Z |
| format | Article |
| id | doaj.art-40668b3ab8d742aca65b34fad1b23dab |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-12T00:30:46Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-40668b3ab8d742aca65b34fad1b23dab2022-12-22T03:55:21ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-12-0110610.1128/spectrum.02949-22Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with FraxetinYunjia Shi0Zeyu Sun1Yang Liu2Jingyan Shu3Yong Zhang4Qianghua Lv5Jianfeng Wang6Xuming Deng7Hongtao Liu8Jiazhang Qiu9State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaDepartment of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Zoonotic Diseases, The First Hospital of Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, ChinaABSTRACT The increasingly serious problem of bacterial drug resistance has led to the development of antivirulence agents. The Salmonella enterica serovar Typhimurium Salmonella pathogenicity island (SPI)-encoded type III secretion system (T3SS) and its effector proteins are important virulence factors for S. Typhimurium invasion and replication in host cells and for antivirulence drug screening. Fraxetin is isolated from Fraxinus spp. Extensive studies have reported its multiple pharmacological activities. However, it remains to be elucidated whether fraxetin affects the function of the S. Typhimurium T3SS. In this study, the anti-infection mechanism of fraxetin on S. Typhimurium and its T3SS was investigated. Fraxetin inhibited the S. Typhimurium invasion of HeLa cells without affecting the growth of bacteria in vitro. Further findings on the mechanism showed that fraxetin had an inhibitory effect on the S. Typhimurium T3SS by inhibiting the transcription of the pathogenesis-related SPI-1 transcriptional activator genes hilD, hilC, and rtsA. Animal experiments showed that fraxetin treatment protected mice against S. Typhimurium infection. Collectively, we provide the first demonstration that fraxetin may serve as an effective T3SS inhibitor for the development of treatments for Salmonella infection. IMPORTANCE The increasingly serious problem of bacterial antibiotic resistance limits the clinical application of antibiotics, which increases the need for the development of antivirulence agents. The type III secretion system (T3SS) plays a critical role in host cell invasion and pathogenesis of Salmonella and becomes a popular target for antivirulence agents screening. Our study found, for the first time, that fraxetin inhibited S. Typhimurium invasion by inhibiting the transcription of genes in a feed-forward regulatory loop. Further in vivo testing showed that fraxetin decreased bacterial burdens in the spleen and liver of S. Typhimurium-infected mice and improved survival outcomes in an in vivo mouse model of S. Typhimurium infection. Collectively, these results demonstrate that fraxetin inhibits S. Typhimurium infection by targeting the T3SS and may serve as a potential agent for the treatment of S. Typhimurium infection.https://journals.asm.org/doi/10.1128/spectrum.02949-22fraxetinS. TyphimuriumSPI-1T3SS |
| spellingShingle | Yunjia Shi Zeyu Sun Yang Liu Jingyan Shu Yong Zhang Qianghua Lv Jianfeng Wang Xuming Deng Hongtao Liu Jiazhang Qiu Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin Microbiology Spectrum fraxetin S. Typhimurium SPI-1 T3SS |
| title | Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin |
| title_full | Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin |
| title_fullStr | Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin |
| title_full_unstemmed | Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin |
| title_short | Inhibition of the Type III Secretion System of Salmonella enterica Serovar Typhimurium via Treatment with Fraxetin |
| title_sort | inhibition of the type iii secretion system of salmonella enterica serovar typhimurium via treatment with fraxetin |
| topic | fraxetin S. Typhimurium SPI-1 T3SS |
| url | https://journals.asm.org/doi/10.1128/spectrum.02949-22 |
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