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dc.contributor.authorIreland, PM
dc.contributor.authorBullifent, HL
dc.contributor.authorSenior, NJ
dc.contributor.authorSouthern, SJ
dc.contributor.authorYang, ZR
dc.contributor.authorIreland, RE
dc.contributor.authorNelson, M
dc.contributor.authorAtkins, HS
dc.contributor.authorTitball, RW
dc.contributor.authorScott, AE
dc.date.accessioned2019-03-29T12:18:21Z
dc.date.issued2019-03-13
dc.description.abstractThe highly virulent intracellular pathogen Francisella tularensis is a Gram-negative bacterium that has a wide host range, including humans, and is the causative agent of tularemia. To identify new therapeutic drug targets and vaccine candidates and investigate the genetic basis of Francisella virulence in the Fischer 344 rat, we have constructed an F. tularensis Schu S4 transposon library. This library consists of more than 300,000 unique transposon mutants and represents a transposon insertion for every 6 bp of the genome. A transposon-directed insertion site sequencing (TraDIS) approach was used to identify 453 genes essential for growth in vitro Many of these essential genes were mapped to key metabolic pathways, including glycolysis/gluconeogenesis, peptidoglycan synthesis, fatty acid biosynthesis, and the tricarboxylic acid (TCA) cycle. Additionally, 163 genes were identified as required for fitness during colonization of the Fischer 344 rat spleen. This in vivo selection screen was validated through the generation of marked deletion mutants that were individually assessed within a competitive index study against the wild-type F. tularensis Schu S4 strain.IMPORTANCE The intracellular bacterial pathogen Francisella tularensis causes a disease in humans characterized by the rapid onset of nonspecific symptoms such as swollen lymph glands, fever, and headaches. F. tularensis is one of the most infectious bacteria known and following pulmonary exposure can have a mortality rate exceeding 50% if left untreated. The low infectious dose of this organism and concerns surrounding its potential as a biological weapon have heightened the need for effective and safe therapies. To expand the repertoire of targets for therapeutic development, we initiated a genome-wide analysis. This study has identified genes that are important for F. tularensis under in vitro and in vivo conditions, providing candidates that can be evaluated for vaccine or antibacterial development.en_GB
dc.description.sponsorshipBiotechnology & Biological Sciences Research Council (BBSRC)en_GB
dc.description.sponsorshipDefence Science and Technology Laboratory (DSTL)en_GB
dc.identifier.citationVol. 201 (7), article e00630-18en_GB
dc.identifier.doi10.1128/JB.00630-18
dc.identifier.grantnumberBB/J004057/1en_GB
dc.identifier.grantnumberDSTLX-1000068994en_GB
dc.identifier.grantnumberDSTLX-1000092991en_GB
dc.identifier.urihttp://hdl.handle.net/10871/36673
dc.language.isoenen_GB
dc.publisherAmerican Society for Microbiologyen_GB
dc.rights© Crown copyright 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.en_GB
dc.subjectessential genesen_GB
dc.subjectFrancisellaen_GB
dc.subjectgene essentialityen_GB
dc.subjectTraDISen_GB
dc.subjecttransposon insertion sequencingen_GB
dc.subjectgenomicsen_GB
dc.subjectvirulenceen_GB
dc.titleGlobal Analysis of Genes Essential for Francisella tularensis Schu S4 Growth In Vitro and for Fitness during Competitive Infection of Fischer 344 Ratsen_GB
dc.typeArticleen_GB
dc.date.available2019-03-29T12:18:21Z
dc.descriptionThis is the final version. Available from American Society for Microbiology via the DOI in this record en_GB
dc.identifier.eissn1098-5530
dc.identifier.journalJournal of Bacteriologyen_GB
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2019-01-02
exeter.funder::Science and Transcendence Advanced Research Seriesen_GB
exeter.funder::Biotechnology & Biological Sciences Research Council (BBSRC)en_GB
exeter.funder::Defence Science and Technology Laboratory (DSTL)en_GB
exeter.funder::Defence Science and Technology Laboratory (DSTL)en_GB
exeter.funder::Defence Science and Technology Laboratory (DSTL)en_GB
rioxxterms.versionAMen_GB
rioxxterms.licenseref.startdate2019-01-02
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2019-03-29T12:14:42Z
refterms.versionFCDAM
refterms.dateFOA2019-03-29T12:18:24Z
refterms.panelAen_GB


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© Crown copyright 2019.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's licence is described as © Crown copyright 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.