RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence.
Burkholderia pseudomallei, the etiological agent of melioidosis in humans and animals, often occupies environmental niches and infection sites characterized by limited concentrations of oxygen. Versatile genomic features enable this pathogen to maintain its physiology and virulence under hypoxia, bu...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009604&type=printable |
| _version_ | 1826554757234294784 |
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| author | Julia Phenn Jan Pané-Farré Nikolai Meukow Annelie Klein Anne Troitzsch Patrick Tan Stephan Fuchs Gabriel E Wagner Sabine Lichtenegger Ivo Steinmetz Christian Kohler |
| author_facet | Julia Phenn Jan Pané-Farré Nikolai Meukow Annelie Klein Anne Troitzsch Patrick Tan Stephan Fuchs Gabriel E Wagner Sabine Lichtenegger Ivo Steinmetz Christian Kohler |
| author_sort | Julia Phenn |
| collection | DOAJ |
| description | Burkholderia pseudomallei, the etiological agent of melioidosis in humans and animals, often occupies environmental niches and infection sites characterized by limited concentrations of oxygen. Versatile genomic features enable this pathogen to maintain its physiology and virulence under hypoxia, but the crucial regulatory networks employed to switch from oxygen dependent respiration to alternative terminal electron acceptors (TEA) like nitrate, remains poorly understood. Here, we combined a Tn5 transposon mutagenesis screen and an anaerobic growth screen to identify a two-component signal transduction system with homology to RegAB. We show that RegAB is not only essential for anaerobic growth, but also for full virulence in cell lines and a mouse infection model. Further investigations of the RegAB regulon, using a global transcriptomic approach, identified 20 additional regulators under transcriptional control of RegAB, indicating a superordinate role of RegAB in the B. pseudomallei anaerobiosis regulatory network. Of the 20 identified regulators, NarX/L and a FNR homolog were selected for further analyses and a role in adaptation to anaerobic conditions was demonstrated. Growth experiments identified nitrate and intermediates of the denitrification process as the likely signal activateing RegAB, NarX/L, and probably of the downstream regulators Dnr or NsrR homologs. While deletions of individual genes involved in the denitrification process demonstrated their important role in anaerobic fitness, they showed no effect on virulence. This further highlights the central role of RegAB as the master regulator of anaerobic metabolism in B. pseudomallei and that the complete RegAB-mediated response is required to achieve full virulence. In summary, our analysis of the RegAB-dependent modulon and its interconnected regulons revealed a key role for RegAB of B. pseudomallei in the coordination of the response to hypoxic conditions and virulence, in the environment and the host. |
| first_indexed | 2024-12-17T19:22:26Z |
| format | Article |
| id | doaj.art-8d8a04c1624445fdbf4619587c704e7e |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2025-03-14T07:45:59Z |
| publishDate | 2021-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-8d8a04c1624445fdbf4619587c704e7e2025-03-03T05:32:21ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-05-01175e100960410.1371/journal.ppat.1009604RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence.Julia PhennJan Pané-FarréNikolai MeukowAnnelie KleinAnne TroitzschPatrick TanStephan FuchsGabriel E WagnerSabine LichteneggerIvo SteinmetzChristian KohlerBurkholderia pseudomallei, the etiological agent of melioidosis in humans and animals, often occupies environmental niches and infection sites characterized by limited concentrations of oxygen. Versatile genomic features enable this pathogen to maintain its physiology and virulence under hypoxia, but the crucial regulatory networks employed to switch from oxygen dependent respiration to alternative terminal electron acceptors (TEA) like nitrate, remains poorly understood. Here, we combined a Tn5 transposon mutagenesis screen and an anaerobic growth screen to identify a two-component signal transduction system with homology to RegAB. We show that RegAB is not only essential for anaerobic growth, but also for full virulence in cell lines and a mouse infection model. Further investigations of the RegAB regulon, using a global transcriptomic approach, identified 20 additional regulators under transcriptional control of RegAB, indicating a superordinate role of RegAB in the B. pseudomallei anaerobiosis regulatory network. Of the 20 identified regulators, NarX/L and a FNR homolog were selected for further analyses and a role in adaptation to anaerobic conditions was demonstrated. Growth experiments identified nitrate and intermediates of the denitrification process as the likely signal activateing RegAB, NarX/L, and probably of the downstream regulators Dnr or NsrR homologs. While deletions of individual genes involved in the denitrification process demonstrated their important role in anaerobic fitness, they showed no effect on virulence. This further highlights the central role of RegAB as the master regulator of anaerobic metabolism in B. pseudomallei and that the complete RegAB-mediated response is required to achieve full virulence. In summary, our analysis of the RegAB-dependent modulon and its interconnected regulons revealed a key role for RegAB of B. pseudomallei in the coordination of the response to hypoxic conditions and virulence, in the environment and the host.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009604&type=printable |
| spellingShingle | Julia Phenn Jan Pané-Farré Nikolai Meukow Annelie Klein Anne Troitzsch Patrick Tan Stephan Fuchs Gabriel E Wagner Sabine Lichtenegger Ivo Steinmetz Christian Kohler RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. PLoS Pathogens |
| title | RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. |
| title_full | RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. |
| title_fullStr | RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. |
| title_full_unstemmed | RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. |
| title_short | RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence. |
| title_sort | regab homolog of burkholderia pseudomallei is the master regulator of redox control and involved in virulence |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009604&type=printable |
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