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To date, the contribution of DksA to <jats:italic>B. burgdorferi<\/jats:italic> infection remains unknown. We report here that DksA is essential for <jats:italic>B. burgdorferi<\/jats:italic> to infect a mammalian host. <jats:italic>dksA<\/jats:italic> expression was highly induced during infection. Moreover, a <jats:italic>dksA<\/jats:italic>\u2010deficient mutant was incapable of infecting mice. The mutant displayed growth defects when cultured in vitro and resistance to osmotic pressure was markedly reduced. These phenotypes were fully restored to those of the wild type when <jats:italic>dksA<\/jats:italic> mutation was complemented. We further showed that DksA controlled the expression of virulence\u2010associated lipoprotein OspC, likely via the central alternative sigma factor RpoS. Synthesis of RpoS was abolished in the <jats:italic>dksA<\/jats:italic> mutant, but <jats:italic>rpoS<\/jats:italic> transcription remained unaffected. Additionally, we found that the expression of <jats:italic>clpX<\/jats:italic>, <jats:italic>clpA<\/jats:italic>, <jats:italic>clpP<\/jats:italic>, and <jats:italic>clpP2<\/jats:italic> was significantly increased in the mutant, suggesting that DksA may post\u2010transcriptionally regulate <jats:italic>rpoS<\/jats:italic> expression via its effect on ClpXP and\/or ClpAP proteases. These combined data demonstrate that DksA regulates <jats:italic>B. burgdorferi<\/jats:italic> virulence at least partially through its influence on RpoS and OspC. This study thus elucidates that, in addition to function as a stringent response regulator, DksA promotes the transcription and\/or translation of genes contributing to <jats:italic>B. burgdorferi<\/jats:italic> infectivity.<\/jats:p>","DOI":"10.1111\/mmi.14504","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T07:12:29Z","timestamp":1585552349000},"page":"172-183","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["DksA plays an essential role in regulating the virulence of <i>Borrelia burgdorferi<\/i>"],"prefix":"10.1111","volume":"114","author":[{"given":"Charlotte","family":"Mason","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine University of South Florida Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine 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