{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:42:07Z","timestamp":1780670527381,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009180","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000}}],"reference-count":120,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Borrelia burgdorferi<\/jats:italic>must acquire all of its amino acids (AAs) from its arthropod vector and vertebrate host. Previously, we determined that peptide uptake via the oligopeptide (Opp) ABC transporter is essential for spirochete viability<jats:italic>in vitro<\/jats:italic>and during infection. Our prior study also suggested that<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>employs temporal regulation in concert with structural variation of oligopeptide-binding proteins (OppAs) to meet its AA requirements in each biological niche. Herein, we evaluated the contributions to the<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>enzootic cycle of three of the spirochete\u2019s five OppAs (OppA1, OppA2, and OppA5). An<jats:italic>oppA1<\/jats:italic>transposon (<jats:italic>tn<\/jats:italic>) mutant lysed in the hyperosmolar environment of the feeding tick, suggesting that OppA1 imports amino acids required for osmoprotection. The<jats:italic>oppA2tn<\/jats:italic>mutant displayed a profound defect in hematogenous dissemination in mice, yet persisted within skin while inducing only a minimal antibody response. These results, along with slightly decreased growth of the<jats:italic>oppA2tn<\/jats:italic>mutant within DMCs, suggest that OppA2 serves a minor nutritive role, while its dissemination defect points to an as yet uncharacterized signaling function. Previously, we identified a role for OppA5 in spirochete persistence within the mammalian host. We now show that the<jats:italic>oppA5tn<\/jats:italic>mutant displayed no defect during the tick phase of the cycle and could be tick-transmitted to na\u00efve mice. Instead of working in tandem, however, OppA2 and OppA5 appear to function in a hierarchical manner; the ability of OppA5 to promote persistence relies upon the ability of OppA2 to facilitate dissemination. Structural homology models demonstrated variations within the binding pockets of OppA1, 2, and 5 indicative of different peptide repertoires. Rather than being redundant,<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>\u2019s multiplicity of Opp binding proteins enables host-specific functional compartmentalization during the spirochete lifecycle.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009180","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T22:37:55Z","timestamp":1610491075000},"page":"e1009180","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Host-specific functional compartmentalization within the oligopeptide transporter during the Borrelia burgdorferi enzootic cycle"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6674-7532","authenticated-orcid":true,"given":"Ashley M.","family":"Groshong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"McLain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin D.","family":"Radolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"issue":"6","key":"ppat.1009180.ref001","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1111\/cmi.12138","article-title":"Microbial quest for food in vivo: 'nutritional virulence' as an emerging paradigm","volume":"15","author":"Y Abu Kwaik","year":"2013","journal-title":"Cell Microbiol"},{"issue":"9","key":"ppat.1009180.ref002","doi-asserted-by":"crossref","first-page":"e1000185","DOI":"10.1371\/journal.pgen.1000185","article-title":"The genome of Borrelia recurrentis, the agent of deadly louse-borne relapsing fever, is a degraded subset of tick-borne Borrelia duttonii","volume":"4","author":"M Lescot","year":"2008","journal-title":"PLoS Genet"},{"issue":"4","key":"ppat.1009180.ref003","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.meegid.2009.02.002","article-title":"Amino acid biosynthesis deficiency in bacteria associated with human and animal hosts","volume":"9","author":"XJ Yu","year":"2009","journal-title":"Infect Genet Evol"},{"key":"ppat.1009180.ref004","article-title":"Interactions between Borrelia burgdorferi and ticks","author":"C Kurokawa","year":"2020","journal-title":"Nat Rev Microbiol"},{"issue":"2","key":"ppat.1009180.ref005","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 Microbiol"},{"key":"ppat.1009180.ref006","first-page":"103","volume-title":"Borrelia Molecular Biology, Host Interactions and Pathogenesis","author":"F Gherardini","year":"2010"},{"issue":"6660","key":"ppat.1009180.ref007","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/37551","article-title":"Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi","volume":"390","author":"CM Fraser","year":"1997","journal-title":"Nature"},{"issue":"9","key":"ppat.1009180.ref008","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.1128\/IAI.00514-12","article-title":"Borrelia burgdorferi harbors a transport system essential for purine salvage and mammalian infection","volume":"80","author":"S Jain","year":"2012","journal-title":"Infect Immun"},{"issue":"1","key":"ppat.1009180.ref009","doi-asserted-by":"crossref","first-page":"e1003109","DOI":"10.1371\/journal.ppat.1003109","article-title":"Lipid exchange between Borrelia burgdorferi and host cells","volume":"9","author":"JT Crowley","year":"2013","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1009180.ref010","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.chom.2010.09.001","article-title":"Cholesterol lipids of Borrelia burgdorferi form lipid rafts and are required for the bactericidal activity of a complement-independent antibody","volume":"8","author":"TJ LaRocca","year":"2010","journal-title":"Cell Host Microbe"},{"issue":"1","key":"ppat.1009180.ref011","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.femsle.2004.12.002","article-title":"Carbohydrate utilization by the Lyme borreliosis spirochete, Borrelia burgdorferi","volume":"243","author":"K von Lackum","year":"2005","journal-title":"FEMS Microbiol Lett"},{"issue":"7","key":"ppat.1009180.ref012","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1111\/cmi.12609","article-title":"Interaction of the Lyme disease spirochete with its tick vector","volume":"18","author":"MJ Caimano","year":"2016","journal-title":"Cell Microbiol"},{"issue":"3","key":"ppat.1009180.ref013","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.MBP-0011-2014","article-title":"Borrelia burgdorferi: carbon metabolism and the tick-mammal enzootic cycle","volume":"3","author":"A Corona","year":"2015","journal-title":"Microbiol Spectr"},{"issue":"6","key":"ppat.1009180.ref014","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.02047-17","article-title":"Peptide uptake is essential for Borrelia burgdorferi viability and involves structural and regulatory complexity of its oligopeptide transporter","volume":"8","author":"AM Groshong","year":"2017","journal-title":"mBio"},{"issue":"3","key":"ppat.1009180.ref015","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0167-4889(00)00121-X","article-title":"Functional testing of putative oligopeptide permease (Opp) proteins of Borrelia burgdorferi: a complementation model in opp(-) Escherichia coli","volume":"1499","author":"B Lin","year":"2001","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"ppat.1009180.ref016","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1128\/JB.186.1.51-60.2004","article-title":"Analysis of differences in the functional properties of the substrate binding proteins of the Borrelia burgdorferi oligopeptide permease (Opp) operon","volume":"186","author":"XG Wang","year":"2004","journal-title":"J Bacteriol"},{"issue":"22","key":"ppat.1009180.ref017","doi-asserted-by":"crossref","first-page":"6198","DOI":"10.1128\/JB.184.22.6198-6206.2002","article-title":"Effects of environmental changes on expression of the oligopeptide permease (opp) genes of Borrelia burgdorferi","volume":"184","author":"XG Wang","year":"2002","journal-title":"J Bacteriol"},{"issue":"8","key":"ppat.1009180.ref018","doi-asserted-by":"crossref","first-page":"e1005791","DOI":"10.1371\/journal.ppat.1005791","article-title":"Two different virulence-related regulatory pathways in Borrelia burgdorferi are directly affected by osmotic fluxes in the blood meal of feeding Ixodes ticks","volume":"12","author":"S Bontemps-Gallo","year":"2016","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1009180.ref019","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1099\/00221287-144-4-1033","article-title":"Oligopeptide permease in Borrelia burgdorferi: putative peptide-binding components encoded by both chromosomal and plasmid loci","volume":"144","author":"JL Bono","year":"1998","journal-title":"Microbiology"},{"issue":"3","key":"ppat.1009180.ref020","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1046\/j.1365-2958.2000.01698.x","article-title":"A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi","volume":"35","author":"S Casjens","year":"2000","journal-title":"Mol Microbiol"},{"issue":"10","key":"ppat.1009180.ref021","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1007\/s00018-003-3054-3","article-title":"Bacterial oligopeptide-binding proteins","volume":"60","author":"V Monnet","year":"2003","journal-title":"Cell Mol Life Sci"},{"issue":"9","key":"ppat.1009180.ref022","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/emboj.2009.65","article-title":"The structural basis for peptide selection by the transport receptor OppA","volume":"28","author":"RP Berntsson","year":"2009","journal-title":"EMBO J"},{"issue":"5165","key":"ppat.1009180.ref023","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1126\/science.8202710","article-title":"The structural basis of sequence-independent peptide binding by OppA protein","volume":"264","author":"JR Tame","year":"1994","journal-title":"Science"},{"issue":"1","key":"ppat.1009180.ref024","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jmb.2011.09.043","article-title":"Escherichia coli peptide binding protein OppA has a preference for positively charged peptides","volume":"414","author":"MM Klepsch","year":"2011","journal-title":"J Mol Biol"},{"issue":"32","key":"ppat.1009180.ref025","doi-asserted-by":"crossref","first-page":"9747","DOI":"10.1021\/bi970457u","article-title":"Peptide binding in OppA, the crystal structures of the periplasmic oligopeptide binding protein in the unliganded form and in complex with lysyllysine","volume":"36","author":"SH Sleigh","year":"1997","journal-title":"Biochemistry"},{"key":"ppat.1009180.ref026","article-title":"Seattle Structural Genomics Center for Infectious Disease (SSGCID)","author":"JW Fairman","year":"2012","journal-title":"X-ray crystal structure of a periplasmic oligopeptide-binding protein\/Oligopeptide ABC transporter(OppAIV) from Borrelia burgdorferi"},{"issue":"2","key":"ppat.1009180.ref027","doi-asserted-by":"crossref","first-page":"e0118063","DOI":"10.1371\/journal.pone.0118063","article-title":"Characterization of the RelBbu regulon in Borrelia burgdorferi reveals modulation of glycerol metabolism by (p)ppGpp","volume":"10","author":"JV Bugrysheva","year":"2015","journal-title":"PLoS One"},{"issue":"22","key":"ppat.1009180.ref028","doi-asserted-by":"crossref","first-page":"7845","DOI":"10.1128\/JB.187.22.7845-7852.2005","article-title":"Alternate sigma factor RpoS is required for the in vivo-specific repression of Borrelia burgdorferi plasmid lp54-borne ospA and lp6.6 genes","volume":"187","author":"MJ Caimano","year":"2005","journal-title":"J Bacteriol"},{"issue":"5","key":"ppat.1009180.ref029","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1111\/j.1365-2958.2007.05860.x","article-title":"Analysis of the RpoS regulon in Borrelia burgdorferi in response to mammalian host signals provides insight into RpoS function during the enzootic cycle","volume":"65","author":"MJ Caimano","year":"2007","journal-title":"Mol Microbiol"},{"issue":"9","key":"ppat.1009180.ref030","doi-asserted-by":"crossref","first-page":"e1005160","DOI":"10.1371\/journal.ppat.1005160","article-title":"The Borrelia burgdorferi RelA\/SpoT homolog and stringent response regulate survival in the tick vector and global gene expression during starvation","volume":"11","author":"D Drecktrah","year":"2015","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1009180.ref031","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/mmi.12882","article-title":"Stage-specific global alterations in the transcriptomes of Lyme disease spirochetes during tick feeding and following mammalian host adaptation","volume":"95","author":"R Iyer","year":"2015","journal-title":"Mol Microbiol"},{"issue":"7","key":"ppat.1009180.ref032","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1128\/JB.01760-06","article-title":"Regulators of expression of the oligopeptide permease A proteins of Borrelia burgdorferi","volume":"189","author":"MS Medrano","year":"2007","journal-title":"J Bacteriol"},{"issue":"9","key":"ppat.1009180.ref033","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1099\/mic.0.2008\/019992-0","article-title":"Transcriptional interplay among the regulators Rrp2, RpoN and RpoS in Borrelia burgdorferi","volume":"154","author":"Z Ouyang","year":"2008","journal-title":"Microbiology"},{"key":"ppat.1009180.ref034","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fcimb.2014.00056","article-title":"The cyclic-di-GMP signaling pathway in the Lyme disease spirochete, Borrelia burgdorferi","volume":"4","author":"EA Novak","year":"2014","journal-title":"Front Cell Infect Microbiol"},{"key":"ppat.1009180.ref035","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1146\/annurev.micro.112408.134040","article-title":"Gene regulation in Borrelia burgdorferi","volume":"65","author":"DS Samuels","year":"2011","journal-title":"Annu Rev Microbiol"},{"key":"ppat.1009180.ref036","first-page":"83","article-title":"Regulation of gene and protein expression in the Lyme disease spirochete","volume":"415","author":"B Stevenson","year":"2018","journal-title":"Curr Top Microbiol Immunol"},{"issue":"8","key":"ppat.1009180.ref037","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1128\/IAI.00315-15","article-title":"Cyclic di-GMP modulates gene expression in Lyme disease spirochetes at the tick-mammal interface to promote spirochete survival during the blood meal and tick-to-mammal transmission","volume":"83","author":"MJ Caimano","year":"2015","journal-title":"Infect Immun"},{"key":"ppat.1009180.ref038","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.3389\/fmicb.2019.01923","article-title":"The RpoS gatekeeper in Borrelia burgdorferi: An invariant regulatory scheme that promotes spirochete persistence in reservoir hosts and niche diversity","volume":"10","author":"MJ Caimano","year":"2019","journal-title":"Front Microbiol"},{"issue":"7","key":"ppat.1009180.ref039","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1128\/IAI.00266-13","article-title":"Understanding barriers to Borrelia burgdorferi dissemination during infection using massively parallel sequencing","volume":"81","author":"EB Troy","year":"2013","journal-title":"Infect Immun"},{"issue":"6","key":"ppat.1009180.ref040","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1111\/mmi.13437","article-title":"Global Tn-seq analysis of carbohydrate utilization and vertebrate infectivity of Borrelia burgdorferi","volume":"101","author":"EB Troy","year":"2016","journal-title":"Mol Microbiol"},{"issue":"10","key":"ppat.1009180.ref041","doi-asserted-by":"crossref","first-page":"e47532","DOI":"10.1371\/journal.pone.0047532","article-title":"Analysis of an ordered, comprehensive STM mutant library in infectious Borrelia burgdorferi: insights into the genes required for mouse infectivity","volume":"7","author":"T Lin","year":"2012","journal-title":"PLoS One"},{"issue":"5","key":"ppat.1009180.ref042","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/j.ttbdis.2018.06.006","article-title":"The oligopeptide ABC transporter OppA4 negatively regulates the virulence factor OspC production of the Lyme disease pathogen","volume":"9","author":"B Zhou","year":"2018","journal-title":"Ticks Tick Borne Dis"},{"issue":"3","key":"ppat.1009180.ref043","first-page":"364","article-title":"orrelia burgdorferi","volume":"40","author":"PF Policastro","year":"2003","journal-title":"J Med Entomol"},{"issue":"5","key":"ppat.1009180.ref044","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00887-18","article-title":"Borrelia burgdorferi bbk13 is critical for spirochete population expansion in the skin during early infection","volume":"87","author":"GF Aranjuez","year":"2019","journal-title":"Infect Immun"},{"issue":"5","key":"ppat.1009180.ref045","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1111\/j.1365-2958.2008.06229.x","article-title":"The global, ppGpp-mediated stringent response to amino acid starvation in Escherichia coli","volume":"68","author":"MF Traxler","year":"2008","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1009180.ref046","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/j.1365-2958.2010.07339.x","article-title":"The global nutritional regulator CodY is an essential protein in the human pathogen Streptococcus pneumoniae","volume":"78","author":"S Caymaris","year":"2010","journal-title":"Mol Microbiol"},{"issue":"4","key":"ppat.1009180.ref047","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1111\/j.1365-2958.2010.07498.x","article-title":"Discretely calibrated regulatory loops controlled by ppGpp partition gene induction across the 'feast to famine' gradient in Escherichia coli","volume":"79","author":"MF Traxler","year":"2011","journal-title":"Mol Microbiol"},{"issue":"14","key":"ppat.1009180.ref048","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1021\/bi300174x","article-title":"Messenger functions of the bacterial cell wall-derived muropeptides","volume":"51","author":"MA Boudreau","year":"2012","journal-title":"Biochemistry"},{"key":"ppat.1009180.ref049","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3389\/fmicb.2019.00500","article-title":"Peptidoglycan muropeptides: Release, perception, and functions as signaling molecules","volume":"10","author":"O Irazoki","year":"2019","journal-title":"Front Microbiol"},{"issue":"3","key":"ppat.1009180.ref050","first-page":"339","article-title":"Peptide conversations in Gram-positive bacteria","volume":"42","author":"V Monnet","year":"2016","journal-title":"Crit Rev Microbiol"},{"issue":"8","key":"ppat.1009180.ref051","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.resmic.2019.07.004","article-title":"The oligopeptide ABC-importers are essential communication channels in Gram-positive bacteria","volume":"170","author":"L Slamti","year":"2019","journal-title":"Res Microbiol"},{"issue":"2","key":"ppat.1009180.ref052","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1574-6976.2007.00094.x","article-title":"Peptidoglycan structure and architecture","volume":"32","author":"W Vollmer","year":"2008","journal-title":"FEMS Microbiol Rev"},{"issue":"26","key":"ppat.1009180.ref053","doi-asserted-by":"crossref","first-page":"10752","DOI":"10.1073\/pnas.0901858106","article-title":"The bactericidal effect of a complement-independent antibody is osmolytic and specific to Borrelia","volume":"106","author":"TJ LaRocca","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ppat.1009180.ref054","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1111\/j.1365-2958.2009.06613.x","article-title":"Comparative cryo-electron tomography of pathogenic Lyme disease spirochetes","volume":"71","author":"M Kudryashev","year":"2009","journal-title":"Mol Microbiol"},{"issue":"1","key":"ppat.1009180.ref055","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0006-291X(90)91734-A","article-title":"Isolation, preliminary chemical characterization, and biological activity of Borrelia burgdorferi peptidoglycan","volume":"167","author":"G Beck","year":"1990","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"ppat.1009180.ref056","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1128\/IAI.00050-13","article-title":"Study of the response regulator Rrp1 reveals its regulatory role in chitobiose utilization and virulence of Borrelia burgdorferi","volume":"81","author":"CW Sze","year":"2013","journal-title":"Infect Immun"},{"issue":"8","key":"ppat.1009180.ref057","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1128\/IAI.05136-11","article-title":"The hybrid histidine kinase Hk1 is part of a two-component system that is essential for survival of Borrelia burgdorferi in feeding Ixodes scapularis ticks","volume":"79","author":"MJ Caimano","year":"2011","journal-title":"Infect Immun"},{"issue":"6","key":"ppat.1009180.ref058","first-page":"e1002133","article-title":"Cyclic di-GMP is essential for the survival of the Lyme disease spirochete in ticks","volume":"7","author":"M He","year":"2011"},{"issue":"1","key":"ppat.1009180.ref059","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1365-2958.2011.07687.x","article-title":"The diguanylate cyclase, Rrp1, regulates critical steps in the enzootic cycle of the Lyme disease spirochetes","volume":"81","author":"JL Kostick","year":"2011","journal-title":"Mol Microbiol"},{"issue":"3","key":"ppat.1009180.ref060","doi-asserted-by":"crossref","DOI":"10.3390\/insects11030201","article-title":"Blood digestion by trypsin-like serine proteases in the replete Lyme disease vector tick, Ixodes scapularis","volume":"11","author":"J Reyes","year":"2020","journal-title":"Insects"},{"issue":"3","key":"ppat.1009180.ref061","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1515\/hsz-2011-0196","article-title":"Development of a host blood meal database: de novo sequencing of hemoglobin from nine small mammals using mass spectrometry","volume":"393","author":"UA Laskay","year":"2012","journal-title":"Biol Chem"},{"issue":"4","key":"ppat.1009180.ref062","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.ttbdis.2015.12.014","article-title":"Multienzyme degradation of host serum albumin in ticks","volume":"7","author":"D Sojka","year":"2016","journal-title":"Ticks Tick Borne Dis"},{"issue":"2","key":"ppat.1009180.ref063","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ibmb.2005.11.005","article-title":"An annotated catalog of salivary gland transcripts from Ixodes scapularis ticks","volume":"36","author":"JM Ribeiro","year":"2006","journal-title":"Insect Biochem Mol Biol"},{"issue":"3","key":"ppat.1009180.ref064","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/mmi.12213","article-title":"The HtrA protease of Borrelia burgdorferi degrades outer membrane protein BmpD and chemotaxis phosphatase CheX","volume":"88","author":"JL Coleman","year":"2013","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1009180.ref065","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/mmi.12377","article-title":"Borrelia burgdorferi BbHtrA degrades host ECM proteins and stimulates release of inflammatory cytokines in vitro","volume":"90","author":"TM Russell","year":"2013","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1009180.ref066","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/mmi.12276","article-title":"Lyme disease spirochaetes possess an aggrecan-binding protease with aggrecanase activity","volume":"90","author":"TM Russell","year":"2013","journal-title":"Mol Microbiol"},{"issue":"7","key":"ppat.1009180.ref067","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1128\/IAI.63.7.2478-2484.1995","article-title":"Borrelia burgdorferi binds plasminogen, resulting in enhanced penetration of endothelial monolayers","volume":"63","author":"JL Coleman","year":"1995","journal-title":"Infect Immun"},{"issue":"2","key":"ppat.1009180.ref068","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3201\/eid0802.010198","article-title":"Vector interactions and molecular adaptations of lyme disease and relapsing fever spirochetes associated with transmission by ticks","volume":"8","author":"TG Schwan","year":"2002","journal-title":"Emerg Infect Dis"},{"issue":"15\u201316","key":"ppat.1009180.ref069","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1007\/s00508-018-1368-2","article-title":"Microbiological features distinguishing Lyme disease and relapsing fever spirochetes","volume":"130","author":"S Bergstrom","year":"2018","journal-title":"Wien Klin Wochenschr"},{"issue":"1","key":"ppat.1009180.ref070","first-page":"3","article-title":"What ticks do under your skin: two-photon intravital imaging of Ixodes scapularis feeding in the presence of the lyme disease spirochete","volume":"87","author":"LK Bockenstedt","year":"2014","journal-title":"Yale J Biol Med"},{"issue":"8","key":"ppat.1009180.ref071","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1128\/JCM.27.8.1723-1727.1989","article-title":"Ear punch biopsy method for detection and isolation of Borrelia burgdorferi from rodents","volume":"27","author":"RJ Sinsky","year":"1989","journal-title":"J Clin Microbiol"},{"issue":"9","key":"ppat.1009180.ref072","doi-asserted-by":"crossref","first-page":"677","DOI":"10.7326\/L16-0409","article-title":"Lyme Disease","volume":"165","author":"LT Hu","year":"2016","journal-title":"Ann Intern Med"},{"key":"ppat.1009180.ref073","first-page":"114","article-title":"Borrelia burgdorferi keeps moving and carries on: A review of borrelial dissemination and invasion","volume":"8","author":"JA Hyde","year":"2017","journal-title":"Front Immunol"},{"issue":"21\u201322","key":"ppat.1009180.ref074","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1007\/s00508-006-0688-9","article-title":"Hematogenous dissemination in early Lyme disease","volume":"118","author":"GP Wormser","year":"2006","journal-title":"Wien Klin Wochenschr"},{"key":"ppat.1009180.ref075","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/978-1-4939-7383-5_18","article-title":"Detection of bioluminescent Borrelia burgdorferi from in Vitro cultivation and during murine infection","volume":"1690","author":"JA Hyde","year":"2018","journal-title":"Methods Mol Biol"},{"issue":"1","key":"ppat.1009180.ref076","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1365-2958.2011.07801.x","article-title":"Bioluminescent imaging of Borrelia burgdorferi in vivo demonstrates that the fibronectin-binding protein BBK32 is required for optimal infectivity","volume":"82","author":"JA Hyde","year":"2011","journal-title":"Mol Microbiol"},{"issue":"9","key":"ppat.1009180.ref077","doi-asserted-by":"crossref","first-page":"e0162501","DOI":"10.1371\/journal.pone.0162501","article-title":"In Vivo imaging demonstrates that Borrelia burgdorferi ospC is uniquely expressed temporally and spatially throughout experimental infection","volume":"11","author":"JT Skare","year":"2016","journal-title":"PLoS One"},{"issue":"3","key":"ppat.1009180.ref078","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.bpj.2013.12.017","article-title":"Spatiotemporal evolution of erythema migrans, the hallmark rash of Lyme disease","volume":"106","author":"DK Vig","year":"2014","journal-title":"Biophys J"},{"issue":"2","key":"ppat.1009180.ref079","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/jgf2.297","article-title":"Large erythema migrans lesion in Lyme disease","volume":"21","author":"Y Takeuchi","year":"2020","journal-title":"J Gen Fam Med"},{"issue":"15\u201316","key":"ppat.1009180.ref080","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00508-018-1376-2","article-title":"Lyme borreliosis, ticks and Borrelia species","volume":"130","author":"G Stanek","year":"2018","journal-title":"Wien Klin Wochenschr"},{"issue":"1","key":"ppat.1009180.ref081","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1001\/archderm.1970.04000070106017","article-title":"Erythema chronicum migrans","volume":"102","author":"RJ Scrimenti","year":"1970","journal-title":"Arch Dermatol"},{"key":"ppat.1009180.ref082","article-title":"CodY, a master integrator of metabolism and virulence in Gram-positive bacteria","author":"SR Brinsmade","year":"2016","journal-title":"Curr Genet"},{"key":"ppat.1009180.ref083","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3389\/fimmu.2016.00442","article-title":"Multifunctional and Redundant Roles of Borrelia burgdorferi Outer Surface Proteins in Tissue Adhesion, Colonization, and Complement Evasion","volume":"7","author":"JA Caine","year":"2016","journal-title":"Front Immunol."},{"issue":"5","key":"ppat.1009180.ref084","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1111\/j.1365-2958.1991.tb01876.x","article-title":"Peptide transport and chemotaxis in Escherichia coli and Salmonella typhimurium: characterization of the dipeptide permease (Dpp) and the dipeptide-binding protein","volume":"5","author":"WN Abouhamad","year":"1991","journal-title":"Mol Microbiol"},{"issue":"11","key":"ppat.1009180.ref085","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1002\/pro.5560041110","article-title":"Crystal structure of the dipeptide binding protein from Escherichia coli involved in active transport and chemotaxis","volume":"4","author":"P Dunten","year":"1995","journal-title":"Protein Sci"},{"issue":"6067","key":"ppat.1009180.ref086","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/321253a0","article-title":"Peptide chemotaxis in E. coli involves the Tap signal transducer and the dipeptide permease","volume":"321","author":"MD Manson","year":"1986","journal-title":"Nature"},{"issue":"5","key":"ppat.1009180.ref087","doi-asserted-by":"crossref","first-page":"616","DOI":"10.4269\/ajtmh.2002.66.616","article-title":"Chemotactic migration of the Lyme disease spirochete (Borrelia burgdorferi) to salivary gland extracts of vector ticks","volume":"66","author":"CM Shih","year":"2002","journal-title":"Am J Trop Med Hyg"},{"issue":"2","key":"ppat.1009180.ref088","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1128\/JB.180.2.231-235.1998","article-title":"Chemotaxis in Borrelia burgdorferi","volume":"180","author":"W Shi","year":"1998","journal-title":"J Bacteriol"},{"issue":"5","key":"ppat.1009180.ref089","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.ttbdis.2019.06.002","article-title":"Borrelia burgdorferi chemotaxis toward tick protein Salp12 contributes to acquisition","volume":"10","author":"KE Murfin","year":"2019","journal-title":"Ticks Tick Borne Dis"},{"issue":"4","key":"ppat.1009180.ref090","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1128\/AEM.01913-06","article-title":"Identification of specific chemoattractants and genetic complementation of a Borrelia burgdorferi chemotaxis mutant: flow cytometry-based capillary tube chemotaxis assay","volume":"73","author":"RG Bakker","year":"2007","journal-title":"Appl Environ Microbiol"},{"issue":"12","key":"ppat.1009180.ref091","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1111\/cmi.12617","article-title":"The Borrelia burgdorferi CheY3 response regulator is essential for chemotaxis and completion of its natural infection cycle","volume":"18","author":"EA Novak","year":"2016","journal-title":"Cell Microbiol"},{"issue":"6","key":"ppat.1009180.ref092","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1128\/IAI.01228-12","article-title":"Motility is crucial for the infectious life cycle of Borrelia burgdorferi","volume":"81","author":"SZ Sultan","year":"2013","journal-title":"Infect Immun"},{"issue":"7","key":"ppat.1009180.ref093","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1128\/IAI.00145-12","article-title":"Borrelia burgdorferi needs chemotaxis to establish infection in mammals and to accomplish its enzootic cycle","volume":"80","author":"CW Sze","year":"2012","journal-title":"Infect Immun"},{"issue":"1","key":"ppat.1009180.ref094","article-title":"Borrelia burgdorferi CheY2 Is Dispensable for Chemotaxis or Motility but Crucial for the Infectious Life Cycle of the Spirochete","volume":"85","author":"H Xu","year":"2017","journal-title":"Infect Immun"},{"issue":"2","key":"ppat.1009180.ref095","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.jaci.2019.03.021","article-title":"The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions","volume":"144","author":"E Guttman-Yassky","year":"2019","journal-title":"J Allergy Clin Immunol"},{"issue":"6","key":"ppat.1009180.ref096","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.4269\/ajtmh.2009.09-0208","article-title":"Niche partitioning of Borrelia burgdorferi and Borrelia miyamotoi in the same tick vector and mammalian reservoir species","volume":"81","author":"AG Barbour","year":"2009","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"ppat.1009180.ref097","doi-asserted-by":"crossref","first-page":"17618","DOI":"10.1038\/s41598-019-54389-3","article-title":"Genomes, expression profiles, and diversity of mitochondria of the White-footed Deermouse Peromyscus leucopus, reservoir of Lyme disease and other zoonoses","volume":"9","author":"AG Barbour","year":"2019","journal-title":"Sci Rep"},{"key":"ppat.1009180.ref098","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.semcdb.2016.07.002","article-title":"Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans","volume":"61","author":"AG Barbour","year":"2017","journal-title":"Semin Cell Dev Biol"},{"issue":"2","key":"ppat.1009180.ref099","doi-asserted-by":"crossref","first-page":"e12885","DOI":"10.1111\/cmi.12885","article-title":"Borrelia burgdorferi protein interactions critical for microbial persistence in mammals","volume":"21","author":"Q Bernard","year":"2019","journal-title":"Cell Microbiol"},{"key":"ppat.1009180.ref100","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fimmu.2017.00116","article-title":"Borrelia burgdorferi manipulates innate and adaptive immunity to establish persistence in rodent reservoir hosts","volume":"8","author":"KE Tracy","year":"2017","journal-title":"Front Immunol"},{"issue":"2","key":"ppat.1009180.ref101","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1074\/jbc.REV119.008583","article-title":"Changing of the guard: How the Lyme disease spirochete subverts the host immune response","volume":"295","author":"G Chaconas","journal-title":"J Biol Chem"},{"issue":"7","key":"ppat.1009180.ref102","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.pt.2020.04.011","article-title":"Complement evasion contributes to Lyme Borreliae-host associations","volume":"36","author":"YP Lin","year":"2020","journal-title":"Trends Parasitol"},{"issue":"6","key":"ppat.1009180.ref103","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.MDNA3-0038-2014","article-title":"vls antigenic variation systems of Lyme disease Borrelia: Eluding host immunity through both random, segmental gene conversion and framework heterogeneity","volume":"2","author":"SJ Norris","year":"2014","journal-title":"Microbiol Spectr"},{"issue":"2","key":"ppat.1009180.ref104","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/vbz.2009.0215","article-title":"Borrelia burgdorferi has minimal impact on the Lyme disease reservoir host Peromyscus leucopus","volume":"11","author":"LE Schwanz","year":"2011","journal-title":"Vector Borne Zoonotic Dis"},{"key":"ppat.1009180.ref105","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.1009180.ref106","volume-title":"Borrelia Molecular Biology, Host Interaction and Pathogenesis","author":"JD Radolf","year":"2010"},{"issue":"12","key":"ppat.1009180.ref107","doi-asserted-by":"crossref","first-page":"7147","DOI":"10.1128\/IAI.72.12.7147-7154.2004","article-title":"BBE02 disruption mutants of Borrelia burgdorferi B31 have a highly transformable, infectious phenotype","volume":"72","author":"H Kawabata","year":"2004","journal-title":"Infect Immun"},{"issue":"5","key":"ppat.1009180.ref108","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1128\/JCM.31.5.1251-1255.1993","article-title":"Standardization of medium for culturing Lyme disease spirochetes","volume":"31","author":"RJ Pollack","year":"1993","journal-title":"J Clin Microbiol"},{"issue":"11","key":"ppat.1009180.ref109","doi-asserted-by":"crossref","first-page":"6433","DOI":"10.1128\/IAI.72.11.6433-6445.2004","article-title":"RpoS is not central to the general stress response in Borrelia burgdorferi but does control expression of one or more essential virulence determinants","volume":"72","author":"MJ Caimano","year":"2004","journal-title":"Infect Immun"},{"issue":"2","key":"ppat.1009180.ref110","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.mimet.2011.05.004","article-title":"Multiplex PCR as a tool for validating plasmid content of Borrelia burgdorferi","volume":"86","author":"I Bunikis","year":"2011","journal-title":"J Microbiol Methods"},{"issue":"13","key":"ppat.1009180.ref111","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1128\/JB.00253-12","article-title":"Rrp2, a prokaryotic enhancer-like binding protein, is essential for viability of Borrelia burgdorferi","volume":"194","author":"AM Groshong","year":"2012","journal-title":"J Bacteriol"},{"issue":"3","key":"ppat.1009180.ref112","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1128\/IAI.72.3.1580-1586.2004","article-title":"Dissolved oxygen levels alter gene expression and antigen profiles in Borrelia burgdorferi","volume":"72","author":"J Seshu","year":"2004","journal-title":"Infect Immun"},{"issue":"6","key":"ppat.1009180.ref113","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1128\/IAI.66.6.2674-2683.1998","article-title":"Decorin-binding protein of Borrelia burgdorferi is encoded within a two-gene operon and is protective in the murine model of Lyme borreliosis","volume":"66","author":"KE Hagman","year":"1998","journal-title":"Infect Immun"},{"issue":"8","key":"ppat.1009180.ref114","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1128\/JB.01802-08","article-title":"Borrelia burgdorferi bba74 is expressed exclusively during tick feeding and is regulated by both arthropod- and mammalian host-specific signals","volume":"191","author":"VB Mulay","year":"2009","journal-title":"J Bacteriol"},{"issue":"4","key":"ppat.1009180.ref115","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2004.10.027","article-title":"TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi","volume":"119","author":"U Pal","year":"2004","journal-title":"Cell"},{"key":"ppat.1009180.ref116","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/978-1-4939-7383-5_3","article-title":"Generation of mammalian host-adapted Borrelia burgdorferi by cultivation in peritoneal dialysis membrane chamber implantation in rats","volume":"1690","author":"MJ Caimano","year":"2018","journal-title":"Methods Mol Biol"},{"issue":"10","key":"ppat.1009180.ref117","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1172\/JCI2325","article-title":"A new animal model for studying Lyme disease spirochetes in a mammalian host-adapted state","volume":"101","author":"DR Akins","year":"1998","journal-title":"J Clin Invest"},{"key":"ppat.1009180.ref118","first-page":"253","article-title":"Electrotransformation of the spirochete Borrelia burgdorferi","volume":"47","author":"DS Samuels","year":"1995","journal-title":"Methods Mol Biol"},{"issue":"12","key":"ppat.1009180.ref119","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1172\/JCI39401","article-title":"Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks","volume":"119","author":"SM Dunham-Ems","year":"2009","journal-title":"J Clin Invest"},{"issue":"25","key":"ppat.1009180.ref120","doi-asserted-by":"crossref","first-page":"13865","DOI":"10.1073\/pnas.97.25.13865","article-title":"Correlation between plasmid content and infectivity in Borrelia burgdorferi","volume":"97","author":"JE Purser","year":"2000","journal-title":"Proc Natl Acad Sci U S A"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1009180","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T12:36:59Z","timestamp":1697546219000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009180"}},"subtitle":[],"editor":[{"given":"Jenifer","family":"Coburn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":120,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1009180","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1009180","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]}}}