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DksA-dependent regulation of RpoS contributes to Borrelia burgdorferi tick-borne transmission and mammalian infectivity

View ORCID ProfileWilliam K. Boyle, View ORCID ProfileCrystal L. Richards, Daniel P. Dulebohn, View ORCID ProfileAmanda K. Zalud, View ORCID ProfileJeff A. Shaw, View ORCID ProfileSándor Lovas, View ORCID ProfileFrank C. Gherardini, View ORCID ProfileTravis J. Bourret
doi: https://doi.org/10.1101/2020.11.04.367946
William K. Boyle
1Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68105
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Crystal L. Richards
2Laboratory of Bacteriology, Gene Regulation Section, Division of Intramural Research, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840
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Daniel P. Dulebohn
2Laboratory of Bacteriology, Gene Regulation Section, Division of Intramural Research, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840
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Amanda K. Zalud
1Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68105
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Jeff A. Shaw
1Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68105
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Sándor Lovas
3Department of Biomedical Sciences, Creighton University, Omaha, NE 68105
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Frank C. Gherardini
2Laboratory of Bacteriology, Gene Regulation Section, Division of Intramural Research, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840
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Travis J. Bourret
1Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68105
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  • For correspondence: travisbourret@creighton.edu
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ABSTRACT

Throughout its enzootic cycle, the Lyme disease spirochete Borreliella (Borrelia) burgdorferi, senses and responds to changes in its environment by using a small repertoire of transcription factors which coordinate the expression of genes required for infection of Ixodes ticks and various mammalian hosts. Among these transcription factors, the DnaK suppressor protein (DksA) plays a pivotal role in regulating gene expression in B. burgdorferi during periods of nutrient limitation and is required for mammalian infectivity. In many pathogenic bacteria, the gene regulatory activity of DksA along with the alarmone guanosine penta- and tetra-phosphate ((p)ppGpp) coordinates the stringent response to various environmental stresses including nutrient limitation. In this study, we sought to characterize the role of DksA in regulating the transcriptional activity of RNA polymerase and in the regulation of RpoS-dependent gene expression required for B. burgdorferi infectivity. Using in vitro transcription assays, we observed recombinant DksA inhibits RpoD-dependent transcription by B. burgdorferi RNA polymerase independent of ppGpp Additionally, we determined the pH-inducible expression of RpoS-dependent genes relies on DksA, but is independent of (p)ppGpp produced by Relbbu. Subsequent transcriptomic and western blot assays indicated DksA regulates the expression of BBD18, a protein previously implicated in the post-transcriptional regulation of RpoS. Moreover, we observed DksA was required for infection of mice following intraperitoneal inoculation or for transmission of B. burgdorferi by Ixodes scapularis nymphs. Together, these data suggest DksA plays a central role in coordinating transcriptional responses of B. burgdorferi required for infectivity through its interactions with RNA polymerase and post-transcriptional control of RpoS.

Author Summary Lyme disease, caused by the spirochetal bacteria Borrelia burgdorferi, is the most common vector-borne illness in North America. The ability of B. burgdorferi to establish infection is predicated by its ability to coordinate the expression of virulence factors in response to diverse environmental stimuli encountered within Ixodes ticks and mammalian hosts. Previous studies have shown an essential role for the alternative sigma factor RpoS in regulating the expression of genes required for the successful transmission of B. burgdorferi by Ixodes ticks and infection of mammalian hosts. The DnaK suppressor protein (DksA) is a global gene regulator in B. burgdorferi that also contributes to the expression of RpoS-dependent genes. In this study, we determined DksA exerts its gene regulatory function through direct interactions with the B. burgdorferi RNA polymerase using in vitro transcription assays and controls the expression of RpoS-dependent genes required for mammalian infection by post-transcriptionally regulating cellular levels of RpoS. Our results demonstrate the utility of in vitro transcription assays to determine how gene regulatory proteins like DksA control gene expression in B. burgdorferi, and reveal a novel role for DksA in the infectious cycle of B. burgdorferi.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 04, 2020.
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DksA-dependent regulation of RpoS contributes to Borrelia burgdorferi tick-borne transmission and mammalian infectivity
William K. Boyle, Crystal L. Richards, Daniel P. Dulebohn, Amanda K. Zalud, Jeff A. Shaw, Sándor Lovas, Frank C. Gherardini, Travis J. Bourret
bioRxiv 2020.11.04.367946; doi: https://doi.org/10.1101/2020.11.04.367946
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DksA-dependent regulation of RpoS contributes to Borrelia burgdorferi tick-borne transmission and mammalian infectivity
William K. Boyle, Crystal L. Richards, Daniel P. Dulebohn, Amanda K. Zalud, Jeff A. Shaw, Sándor Lovas, Frank C. Gherardini, Travis J. Bourret
bioRxiv 2020.11.04.367946; doi: https://doi.org/10.1101/2020.11.04.367946

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