An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions
Abstract Background The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regula...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-07-01
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| Series: | BMC Microbiology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12866-017-1073-8 |
| _version_ | 1818981014179938304 |
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| author | Nicola J. Senior Kalesh Sasidharan Richard J. Saint Andrew E. Scott Mitali Sarkar-Tyson Philip M. Ireland Helen L Bullifent Z. Rong Yang Karen Moore Petra C. F. Oyston Timothy P. Atkins Helen S. Atkins Orkun S. Soyer Richard W. Titball |
| author_facet | Nicola J. Senior Kalesh Sasidharan Richard J. Saint Andrew E. Scott Mitali Sarkar-Tyson Philip M. Ireland Helen L Bullifent Z. Rong Yang Karen Moore Petra C. F. Oyston Timothy P. Atkins Helen S. Atkins Orkun S. Soyer Richard W. Titball |
| author_sort | Nicola J. Senior |
| collection | DOAJ |
| description | Abstract Background The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regulates virulence of the bacterium. The bacterium normally grows outside the human host at 28 °C. Therefore, understanding the mechanisms that the bacterium used to adapt to a mammalian host at 37 °C is central to the development of vaccines or drugs for the prevention or treatment of human disease. Results Using a library of over 1 million Y. pestis CO92 random mutants and transposon-directed insertion site sequencing, we identified 530 essential genes when the bacteria were cultured at 28 °C. When the library of mutants was subsequently cultured at 37 °C we identified 19 genes that were essential at 37 °C but not at 28 °C, including genes which encode proteins that play a role in enabling functioning of the type III secretion and in DNA replication and maintenance. Using genome-scale metabolic network reconstruction we showed that growth conditions profoundly influence the physiology of the bacterium, and by combining computational and experimental approaches we were able to identify 54 genes that are essential under a broad range of conditions. Conclusions Using an integrated computational-experimental approach we identify genes which are required for growth at 37 °C and under a broad range of environments may be the best targets for the development of new interventions to prevent or treat plague in humans. |
| first_indexed | 2024-12-20T17:24:35Z |
| format | Article |
| id | doaj.art-1ac8f1a3fcab47d2ad8d2ad511b68c40 |
| institution | Directory Open Access Journal |
| issn | 1471-2180 |
| language | English |
| last_indexed | 2024-12-20T17:24:35Z |
| publishDate | 2017-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj.art-1ac8f1a3fcab47d2ad8d2ad511b68c402022-12-21T19:31:38ZengBMCBMC Microbiology1471-21802017-07-0117111210.1186/s12866-017-1073-8An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditionsNicola J. Senior0Kalesh Sasidharan1Richard J. Saint2Andrew E. Scott3Mitali Sarkar-Tyson4Philip M. Ireland5Helen L Bullifent6Z. Rong Yang7Karen Moore8Petra C. F. Oyston9Timothy P. Atkins10Helen S. Atkins11Orkun S. Soyer12Richard W. Titball13College of Life and Environmental Sciences, University of ExeterSchool of Life Sciences, University of WarwickDefence Science Technology LaboratoryDefence Science Technology LaboratoryDefence Science Technology LaboratoryDefence Science Technology LaboratoryDefence Science Technology LaboratoryCollege of Life and Environmental Sciences, University of ExeterCollege of Life and Environmental Sciences, University of ExeterDefence Science Technology LaboratoryCollege of Life and Environmental Sciences, University of ExeterCollege of Life and Environmental Sciences, University of ExeterSchool of Life Sciences, University of WarwickCollege of Life and Environmental Sciences, University of ExeterAbstract Background The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regulates virulence of the bacterium. The bacterium normally grows outside the human host at 28 °C. Therefore, understanding the mechanisms that the bacterium used to adapt to a mammalian host at 37 °C is central to the development of vaccines or drugs for the prevention or treatment of human disease. Results Using a library of over 1 million Y. pestis CO92 random mutants and transposon-directed insertion site sequencing, we identified 530 essential genes when the bacteria were cultured at 28 °C. When the library of mutants was subsequently cultured at 37 °C we identified 19 genes that were essential at 37 °C but not at 28 °C, including genes which encode proteins that play a role in enabling functioning of the type III secretion and in DNA replication and maintenance. Using genome-scale metabolic network reconstruction we showed that growth conditions profoundly influence the physiology of the bacterium, and by combining computational and experimental approaches we were able to identify 54 genes that are essential under a broad range of conditions. Conclusions Using an integrated computational-experimental approach we identify genes which are required for growth at 37 °C and under a broad range of environments may be the best targets for the development of new interventions to prevent or treat plague in humans.http://link.springer.com/article/10.1186/s12866-017-1073-8Yersinia pestisPlagueTRADISTransposonEssential genesMetabolic model |
| spellingShingle | Nicola J. Senior Kalesh Sasidharan Richard J. Saint Andrew E. Scott Mitali Sarkar-Tyson Philip M. Ireland Helen L Bullifent Z. Rong Yang Karen Moore Petra C. F. Oyston Timothy P. Atkins Helen S. Atkins Orkun S. Soyer Richard W. Titball An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions BMC Microbiology Yersinia pestis Plague TRADIS Transposon Essential genes Metabolic model |
| title | An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| title_full | An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| title_fullStr | An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| title_full_unstemmed | An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| title_short | An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| title_sort | integrated computational experimental approach reveals yersinia pestis genes essential across a narrow or a broad range of environmental conditions |
| topic | Yersinia pestis Plague TRADIS Transposon Essential genes Metabolic model |
| url | http://link.springer.com/article/10.1186/s12866-017-1073-8 |
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