{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:17:59Z","timestamp":1790745479528,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009725","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000}}],"reference-count":123,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T00:00:00Z","timestamp":1626307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI029735"],"award-info":[{"award-number":["AI029735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI029735"],"award-info":[{"award-number":["AI029735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI39940"],"award-info":[{"award-number":["AI39940"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI39940"],"award-info":[{"award-number":["AI39940"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI126146"],"award-info":[{"award-number":["AI126146"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014731","name":"Global Lyme Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Connecticut Children's Medical Center"},{"name":"Connecticut Children's Medical Center"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>In this study, we examined the relationship between c-di-GMP and its only known effector protein, PlzA, in <jats:italic>Borrelia burgdorferi<\/jats:italic> during the arthropod and mammalian phases of the enzootic cycle. Using a <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic> strain expressing a <jats:italic>plzA<\/jats:italic> point mutant (<jats:italic>plzA-R145D<\/jats:italic>) unable to bind c-di-GMP, we confirmed that the protective function of PlzA in ticks is c-di-GMP-dependent. Unlike \u0394<jats:italic>plzA<\/jats:italic> spirochetes, which are severely attenuated in mice, the <jats:italic>plzA-R145D<\/jats:italic> strain was fully infectious, firmly establishing that PlzA serves a c-di-GMP-independent function in mammals. Contrary to prior reports, loss of PlzA did not affect expression of RpoS or RpoS-dependent genes, which are essential for transmission, mammalian host-adaptation and murine infection. To ascertain the nature of PlzA\u2019s c-di-GMP-independent function(s), we employed infection models using (i) host-adapted mutant spirochetes for needle inoculation of immunocompetent mice and (ii) infection of <jats:italic>scid<\/jats:italic> mice with <jats:italic>in vitro<\/jats:italic>-grown organisms. Both approaches substantially restored \u0394<jats:italic>plzA<\/jats:italic> infectivity, suggesting that PlzA enables <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic> to overcome an early bottleneck to infection. Furthermore, using a <jats:italic>Borrelia<\/jats:italic> strain expressing a heterologous, constitutively active diguanylate cyclase, we demonstrate that \u2018ectopic\u2019 production of c-di-GMP in mammals abrogates spirochete virulence and interferes with RpoS function at the post-translational level in a PlzA-dependent manner. Structural modeling and SAXS analysis of liganded- and unliganded-PlzA revealed marked conformational changes that underlie its biphasic functionality. This structural plasticity likely enables PlzA to serve as a c-di-GMP biosensor that in its respective liganded and unliganded states promote vector- and host-adaptation by the Lyme disease spirochete.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009725","type":"journal-article","created":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T17:46:51Z","timestamp":1626371211000},"page":"e1009725","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["PlzA is a bifunctional c-di-GMP biosensor that promotes tick and mammalian host-adaptation of Borrelia burgdorferi"],"prefix":"10.1371","volume":"17","author":[{"given":"Ashley M.","family":"Groshong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-2165","authenticated-orcid":true,"given":"Andr\u00e9 A.","family":"Grassmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Luthra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"McLain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9091-3740","authenticated-orcid":true,"given":"Anthony A.","family":"Provatas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin D.","family":"Radolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-4102","authenticated-orcid":true,"given":"Melissa J.","family":"Caimano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,15]]},"reference":[{"key":"ppat.1009725.ref001","doi-asserted-by":"crossref","first-page":"16090","DOI":"10.1038\/nrdp.2016.90","article-title":"Lyme borreliosis","volume":"2","author":"AC Steere","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"ppat.1009725.ref002","first-page":"333","article-title":"Lyme Disease in Humans","volume":"42","author":"JD Radolf","year":"2021","journal-title":"Curr Issues Mol Biol"},{"issue":"2","key":"ppat.1009725.ref003","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nrmicro2714","article-title":"Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes","volume":"10","author":"JD Radolf","year":"2012","journal-title":"Nat Rev 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