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Chlamydia trachomatis In Vivo to In Vitro Transition Reveals Mechanisms of Phase Variation and Down-Regulation of Virulence Factors

2015-07-24Journal article Open access
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dc.contributor.authorBorges, Vítor
dc.contributor.authorPinheiro, Miguel
dc.contributor.authorAntelo, Minia
dc.contributor.authorSampaio, Daniel A.
dc.contributor.authorVieira, Luís
dc.contributor.authorFerreira, Rita
dc.contributor.authorNunes, Alexandra
dc.contributor.authorAlmeida, Filipe
dc.contributor.authorMota, Luís J.
dc.contributor.authorBorrego, Maria José
dc.contributor.authorGomes, João Paulo
dc.date.accessioned2016-02-19T15:09:32Z
dc.date.available2016-02-19T15:09:32Z
dc.date.issued2015-07-24
dc.description.abstractResearch on the obligate intracellular bacterium Chlamydia trachomatis demands culture in cell-lines, but the adaptive process behind the in vivo to in vitro transition is not understood. We assessed the genomic and transcriptomic dynamics underlying C. trachomatis in vitro adaptation of strains representing the three disease groups (ocular, epithelial-genital and lymphogranuloma venereum) propagated in epithelial cells over multiple passages. We found genetic features potentially underlying phase variation mechanisms mediating the regulation of a lipid A biosynthesis enzyme (CT533/LpxC), and the functionality of the cytotoxin (CT166) through an ON/OFF mechanism. We detected inactivating mutations in CT713/porB, a scenario suggesting metabolic adaptation to the available carbon source. CT135 was inactivated in a tropism-specific manner, with CT135-negative clones emerging for all epithelial-genital populations (but not for LGV and ocular populations) and rapidly increasing in frequency (~23% mutants per 10 passages). RNA-sequencing analyses revealed that a deletion event involving CT135 impacted the expression of multiple virulence factors, namely effectors known to play a role in the C. trachomatis host-cell invasion or subversion (e.g., CT456/Tarp, CT694, CT875/TepP and CT868/ChlaDub1). This reflects a scenario of attenuation of C. trachomatis virulence in vitro, which may take place independently or in a cumulative fashion with the also observed down-regulation of plasmid-related virulence factors. This issue may be relevant on behalf of the recent advances in Chlamydia mutagenesis and transformation where culture propagation for selecting mutants/transformants is mandatory. Finally, there was an increase in the growth rate for all strains, reflecting gradual fitness enhancement over time. In general, these data shed light on the adaptive process underlying the C. trachomatis in vivo to in vitro transition, and indicates that it would be prudent to restrict culture propagation to minimal passages and check the status of the CT135 genotype in order to avoid the selection of CT135-negative mutants, likely originating less virulent strains.pt_PT
dc.description.sponsorshipVB was a recipient of Ph.D. fellowship (SFRH/BD/68527/2010) from Fundação para a Ciência e a Tecnologia (FCT). MP is funded by a Wellcome Trust ISSF grant (097831/Z/11/Z). RF and AN are recipients of a Ph.D. (SFRH/BD/68532/2010) and post-doctoral fellowships (SFRH/BPD/75295/2010) from FCT, respectively.pt_PT
dc.identifier.citationPLoS One. 2015 Jul 24;10(7):e0133420. doi: 10.1371/journal.pone.0133420. eCollection 2015pt_PT
dc.identifier.doi10.1371/journal.pone.0133420pt_PT
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.18/3442
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relation.publisherversionhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133420pt_PT
dc.subjectChlamydia trachomatispt_PT
dc.subjectCT135pt_PT
dc.subjectIn vivopt_PT
dc.subjectPhase Variationpt_PT
dc.subjectInfecções Sexualmente Transmissíveispt_PT
dc.titleChlamydia trachomatis In Vivo to In Vitro Transition Reveals Mechanisms of Phase Variation and Down-Regulation of Virulence Factorspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titlePLoS Onept_PT
oaire.citation.volume10(7)pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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