Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen
ABSTRACT In Borrelia burgdorferi, the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σS). Understanding the regulation of RpoS is crucial for elucidating how B. burgdorferi is maintained throughout its enzootic cycle. Our rec...
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| Language: | English |
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American Society for Microbiology
2025-03-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02766-24 |
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| author | Sajith Raghunandanan Raj Priya Gaofeng Lin Fuad Alanazi Andrew Zoss Elise Warren Philip Stewart X. Frank Yang |
| author_facet | Sajith Raghunandanan Raj Priya Gaofeng Lin Fuad Alanazi Andrew Zoss Elise Warren Philip Stewart X. Frank Yang |
| author_sort | Sajith Raghunandanan |
| collection | DOAJ |
| description | ABSTRACT In Borrelia burgdorferi, the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σS). Understanding the regulation of RpoS is crucial for elucidating how B. burgdorferi is maintained throughout its enzootic cycle. Our recent studies have shown that the homolog of Fur/PerR repressor/activator BosR functions as an RNA-binding protein that controls the rpoS mRNA stability. However, the mechanisms regulating BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we uncovered a positive feedback loop between RpoS and BosR, wherein RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion of rpoS significantly reduced BosR levels, whereas artificial induction of rpoS resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect bosR mRNA levels but instead modulates the turnover rate of the BosR protein. Moreover, we demonstrated that environmental cues do not directly influence bosR expression but instead induce rpoS transcription and RpoS production, thereby enhancing BosR protein levels. These findings reveal a new layer of complexity in the RpoN-RpoS regulatory pathway, challenging the existing paradigm and suggesting a need to re-evaluate the factors and signals previously implicated in regulating RpoS via BosR. This study provides new insights into the intricate regulatory networks underpinning B. burgdorferi’s adaptation and survival in its enzootic cycle.IMPORTANCELyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent, Borreliella (or Borrelia) burgdorferi, is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection of B. burgdorferi. This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disrupt B. burgdorferi’s enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria. |
| format | Article |
| id | doaj-art-a79b69b6867b4acc94f9fab058089b72 |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-a79b69b6867b4acc94f9fab058089b722025-08-20T02:59:06ZengAmerican Society for MicrobiologymBio2150-75112025-03-0116310.1128/mbio.02766-24Positive feedback regulation between RpoS and BosR in the Lyme disease pathogenSajith Raghunandanan0Raj Priya1Gaofeng Lin2Fuad Alanazi3Andrew Zoss4Elise Warren5Philip Stewart6X. Frank Yang7Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USABiology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USADepartment of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USAABSTRACT In Borrelia burgdorferi, the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σS). Understanding the regulation of RpoS is crucial for elucidating how B. burgdorferi is maintained throughout its enzootic cycle. Our recent studies have shown that the homolog of Fur/PerR repressor/activator BosR functions as an RNA-binding protein that controls the rpoS mRNA stability. However, the mechanisms regulating BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we uncovered a positive feedback loop between RpoS and BosR, wherein RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion of rpoS significantly reduced BosR levels, whereas artificial induction of rpoS resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect bosR mRNA levels but instead modulates the turnover rate of the BosR protein. Moreover, we demonstrated that environmental cues do not directly influence bosR expression but instead induce rpoS transcription and RpoS production, thereby enhancing BosR protein levels. These findings reveal a new layer of complexity in the RpoN-RpoS regulatory pathway, challenging the existing paradigm and suggesting a need to re-evaluate the factors and signals previously implicated in regulating RpoS via BosR. This study provides new insights into the intricate regulatory networks underpinning B. burgdorferi’s adaptation and survival in its enzootic cycle.IMPORTANCELyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent, Borreliella (or Borrelia) burgdorferi, is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection of B. burgdorferi. This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disrupt B. burgdorferi’s enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria.https://journals.asm.org/doi/10.1128/mbio.02766-24Lyme diseaseBorrelia burgdorferiRpoSBosRtick-borne pathogens |
| spellingShingle | Sajith Raghunandanan Raj Priya Gaofeng Lin Fuad Alanazi Andrew Zoss Elise Warren Philip Stewart X. Frank Yang Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen mBio Lyme disease Borrelia burgdorferi RpoS BosR tick-borne pathogens |
| title | Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen |
| title_full | Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen |
| title_fullStr | Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen |
| title_full_unstemmed | Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen |
| title_short | Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen |
| title_sort | positive feedback regulation between rpos and bosr in the lyme disease pathogen |
| topic | Lyme disease Borrelia burgdorferi RpoS BosR tick-borne pathogens |
| url | https://journals.asm.org/doi/10.1128/mbio.02766-24 |
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