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Understanding the regulation of RpoS is crucial for elucidating how\n                      <jats:italic>B. burgdorferi<\/jats:italic>\n                      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\n                      <jats:italic>rpoS<\/jats:italic>\n                      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\n                      <jats:italic>rpoS<\/jats:italic>\n                      significantly reduced BosR levels, whereas artificial induction of\n                      <jats:italic>rpoS<\/jats:italic>\n                      resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect\n                      <jats:italic>bosR<\/jats:italic>\n                      mRNA levels but instead modulates the turnover rate of the BosR protein. Moreover, we demonstrated that environmental cues do not directly influence\n                      <jats:italic>bosR<\/jats:italic>\n                      expression but instead induce\n                      <jats:italic>rpoS<\/jats:italic>\n                      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\n                      <jats:italic>B. burgdorferi<\/jats:italic>\n                      \u2019s adaptation and survival in its enzootic cycle.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Lyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent,\n                        <jats:italic>Borreliella<\/jats:italic>\n                        (or\n                        <jats:italic>Borrelia<\/jats:italic>\n                        )\n                        <jats:italic>burgdorferi<\/jats:italic>\n                        , 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\n                        <jats:italic>B. burgdorferi<\/jats:italic>\n                        . 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\n                        <jats:italic>B. burgdorferi<\/jats:italic>\n                        \u2019s enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur\/PerR family in other bacteria.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02766-24","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T09:00:49Z","timestamp":1738054849000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-307X","authenticated-orcid":false,"given":"Sajith","family":"Raghunandanan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Priya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaofeng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5328-6239","authenticated-orcid":true,"given":"Fuad","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]},{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Zoss","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Warren","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Stewart","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Hamilton, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-3167","authenticated-orcid":true,"given":"X. 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