The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli
Abstract Background Extraintestinal pathogenic E. coli (ExPEC) remains one of the most prevalent bacterial pathogens that cause extraintestinal infections, including neonatal meningitis, septicemia, and urinary tract (UT) infections (UTIs). Antibiotic therapy has been the conventional treatment for...
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| Format: | Article |
| Language: | English |
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BMC
2020-01-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-019-0605-y |
| _version_ | 1818953042150555648 |
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| author | Wen-Chun Huang Chung-Yen Lin Masayuki Hashimoto Jiunn-Jong Wu Ming-Cheng Wang Wei-Hung Lin Chang-Shi Chen Ching-Hao Teng |
| author_facet | Wen-Chun Huang Chung-Yen Lin Masayuki Hashimoto Jiunn-Jong Wu Ming-Cheng Wang Wei-Hung Lin Chang-Shi Chen Ching-Hao Teng |
| author_sort | Wen-Chun Huang |
| collection | DOAJ |
| description | Abstract Background Extraintestinal pathogenic E. coli (ExPEC) remains one of the most prevalent bacterial pathogens that cause extraintestinal infections, including neonatal meningitis, septicemia, and urinary tract (UT) infections (UTIs). Antibiotic therapy has been the conventional treatment for such infections, but its efficacy has decreased due to the emergence of antibiotic-resistant bacteria. Identification and characterization of bacterial factors that contribute to the severity of infection would facilitate the development of novel therapeutic strategies. The ExPEC periplasmic protease Prc contributes to the pathogen’s ability to evade complement-mediated killing in the serum. Here, we further investigated the role of the Prc protease in ExPEC-induced UTIs and the underlying mechanism. Methods The uropathogenic role of Prc was determined in a mouse model of UTIs. Using global quantitative proteomic analyses, we revealed that the expression of FliC and other outer membrane-associated proteins was altered by Prc deficiency. Comparative transcriptome analyses identified that Prc deficiency affected expression of the flagellar regulon and genes that are regulated by five extracytoplasmic signaling systems. Results A mutant ExPEC with a prc deletion was attenuated in bladder and kidney colonization. Global quantitative proteomic analyses of the prc mutant and wild-type ExPEC strains revealed significantly reduced flagellum expression in the absence of Prc, consequently impairing bacterial motility. The prc deletion triggered downregulation of the flhDC operon encoding the master transcriptional regulator of flagellum biogenesis. Overexpressing flhDC restored the prc mutant’s motility and ability to colonize the UT, suggesting that the impaired motility is responsible for attenuated UT colonization of the mutant. Further comparative transcriptome analyses revealed that Prc deficiency activated the σE and RcsCDB signaling pathways. These pathways were responsible for the diminished flhDC expression. Finally, the activation of the RcsCDB system was attributed to the intracellular accumulation of a known Prc substrate Spr in the prc mutant. Spr is a peptidoglycan hydrolase and its accumulation destabilizes the bacterial envelope. Conclusions We demonstrated for the first time that Prc is essential for full ExPEC virulence in UTIs. Our results collectively support the idea that Prc is essential for bacterial envelope integrity, thus explaining how Prc deficiency results in an attenuated ExPEC. |
| first_indexed | 2024-12-20T09:59:59Z |
| format | Article |
| id | doaj.art-6b0cff1c2994467392c491e07d0cee1a |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-12-20T09:59:59Z |
| publishDate | 2020-01-01 |
| publisher | BMC |
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| series | Journal of Biomedical Science |
| spelling | doaj.art-6b0cff1c2994467392c491e07d0cee1a2022-12-21T19:44:21ZengBMCJournal of Biomedical Science1423-01272020-01-0127112210.1186/s12929-019-0605-yThe role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coliWen-Chun Huang0Chung-Yen Lin1Masayuki Hashimoto2Jiunn-Jong Wu3Ming-Cheng Wang4Wei-Hung Lin5Chang-Shi Chen6Ching-Hao Teng7Institute of Molecular Medicine, College of Medicine, National Cheng Kung UniversityInstitute of Information Science, Academia SinicaInstitute of Molecular Medicine, College of Medicine, National Cheng Kung UniversityDepartment of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming UniversityDepartment of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityInstitute of Molecular Medicine, College of Medicine, National Cheng Kung UniversityAbstract Background Extraintestinal pathogenic E. coli (ExPEC) remains one of the most prevalent bacterial pathogens that cause extraintestinal infections, including neonatal meningitis, septicemia, and urinary tract (UT) infections (UTIs). Antibiotic therapy has been the conventional treatment for such infections, but its efficacy has decreased due to the emergence of antibiotic-resistant bacteria. Identification and characterization of bacterial factors that contribute to the severity of infection would facilitate the development of novel therapeutic strategies. The ExPEC periplasmic protease Prc contributes to the pathogen’s ability to evade complement-mediated killing in the serum. Here, we further investigated the role of the Prc protease in ExPEC-induced UTIs and the underlying mechanism. Methods The uropathogenic role of Prc was determined in a mouse model of UTIs. Using global quantitative proteomic analyses, we revealed that the expression of FliC and other outer membrane-associated proteins was altered by Prc deficiency. Comparative transcriptome analyses identified that Prc deficiency affected expression of the flagellar regulon and genes that are regulated by five extracytoplasmic signaling systems. Results A mutant ExPEC with a prc deletion was attenuated in bladder and kidney colonization. Global quantitative proteomic analyses of the prc mutant and wild-type ExPEC strains revealed significantly reduced flagellum expression in the absence of Prc, consequently impairing bacterial motility. The prc deletion triggered downregulation of the flhDC operon encoding the master transcriptional regulator of flagellum biogenesis. Overexpressing flhDC restored the prc mutant’s motility and ability to colonize the UT, suggesting that the impaired motility is responsible for attenuated UT colonization of the mutant. Further comparative transcriptome analyses revealed that Prc deficiency activated the σE and RcsCDB signaling pathways. These pathways were responsible for the diminished flhDC expression. Finally, the activation of the RcsCDB system was attributed to the intracellular accumulation of a known Prc substrate Spr in the prc mutant. Spr is a peptidoglycan hydrolase and its accumulation destabilizes the bacterial envelope. Conclusions We demonstrated for the first time that Prc is essential for full ExPEC virulence in UTIs. Our results collectively support the idea that Prc is essential for bacterial envelope integrity, thus explaining how Prc deficiency results in an attenuated ExPEC.https://doi.org/10.1186/s12929-019-0605-yExtraintestinal pathogenic Escherichia coliUrinary tract infectionsProtease PrcMotilityFlagellaσE |
| spellingShingle | Wen-Chun Huang Chung-Yen Lin Masayuki Hashimoto Jiunn-Jong Wu Ming-Cheng Wang Wei-Hung Lin Chang-Shi Chen Ching-Hao Teng The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli Journal of Biomedical Science Extraintestinal pathogenic Escherichia coli Urinary tract infections Protease Prc Motility Flagella σE |
| title | The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli |
| title_full | The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli |
| title_fullStr | The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli |
| title_full_unstemmed | The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli |
| title_short | The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli |
| title_sort | role of the bacterial protease prc in the uropathogenesis of extraintestinal pathogenic escherichia coli |
| topic | Extraintestinal pathogenic Escherichia coli Urinary tract infections Protease Prc Motility Flagella σE |
| url | https://doi.org/10.1186/s12929-019-0605-y |
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