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However, factors that enable the pathogen to cross the blood-brain barrier (BBB) and invade the central nervous system (CNS) are still not well understood. The objective of this study was to identify the\n            <jats:italic>B. burgdorferi<\/jats:italic>\n            factors required for BBB transmigration. We utilized a transwell BBB model based on human brain-microvascular endothelial cells and focused on investigating the Rrp2-RpoN-RpoS pathway, a central regulatory pathway that is essential for mammalian infection by\n            <jats:italic>B. burgdorferi<\/jats:italic>\n            . Our results demonstrated that the Rrp2-RpoN-RpoS pathway is crucial for BBB transmigration. Furthermore, we identified OspC, a major surface lipoprotein controlled by the Rrp2-RpoN-RpoS pathway, as a significant contributor to BBB transmigration. Constitutive production of OspC in a mutant defective in the Rrp2-RpoN-RpoS pathway did not rescue the impairment in BBB transmigration, indicating that this pathway controls additional factors for this process. Two other major surface lipoproteins controlled by this pathway, DbpA\/B and BBK32, appeared to be dispensable for BBB transmigration. In addition, both the surface lipoprotein OspA and the Rrp1 pathway, which are required\n            <jats:italic>B. burgdorferi<\/jats:italic>\n            colonization in the tick vector, were found not required for BBB transmigration. Collectively, our findings using\n            <jats:italic>in vitro<\/jats:italic>\n            transwell assays uncover another potential role of the Rrp2-RpoN-RpoS pathway in BBB transmigration of\n            <jats:italic>B. burgdorferi<\/jats:italic>\n            and invasion into the CNS.\n          <\/jats:p>","DOI":"10.1128\/iai.00227-23","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T13:00:19Z","timestamp":1698152419000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["The Rrp2-RpoN-RpoS pathway plays an important role in the blood-brain barrier transmigration of the Lyme disease pathogen"],"prefix":"10.1128","volume":"91","author":[{"given":"Fuad","family":"Alanazi","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana, USA"},{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University , Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-307X","authenticated-orcid":false,"given":"Sajith","family":"Raghunandanan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Priya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-3167","authenticated-orcid":true,"given":"X. 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