Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

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dc.contributor.authorLlobet, Enrique
dc.contributor.authorMartínez Moliner, Verónica
dc.contributor.authorMoranta, David
dc.contributor.authorDahlström, Käthe M.
dc.contributor.authorRegueiro, Verónica
dc.contributor.authorTomás, Anna
dc.contributor.authorCano, Victoria
dc.contributor.authorPérez Gutiérrez, Camino
dc.contributor.authorFrank, Christian G.
dc.contributor.authorGarmendia García, Juncal
dc.contributor.departmentIdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutuaes_ES
dc.date.accessioned2018-12-28T09:14:07Z
dc.date.available2018-12-28T09:14:07Z
dc.date.issued2015
dc.description.abstractThe outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacylmodified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrugresistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO-dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.en
dc.description.sponsorshipThis work was also supported by a Spanish Ministry of Economy and Competitiveness Grant (Biomedicine Programme, SAF2012-39841), Marie Curie Career Integration Grant U-KARE (PCIG13-GA-2013-618162), and Queen’s University Belfast start-up funds (to J.A.B.).en
dc.format.extent10 p.
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.identifier.doi10.1073/pnas.1508820112
dc.identifier.issn0027-8424 (Print)
dc.identifier.issn1091-6490 (Electronic)
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/31891
dc.language.isoengen
dc.publisherNational Academy of Sciencesen
dc.relation.ispartofPNAS November 17, 2015 112 (46) E6369-E6378en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2012-39841/ES/
dc.relation.publisherversionhttps://doi.org/10.1073/pnas.1508820112
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.subjectLipid Aen
dc.subjectKlebsiellaen
dc.subjectColistinen
dc.subjectLpxOen
dc.subjectPhoPQen
dc.titleDeciphering tissue-induced Klebsiella pneumoniae lipid A structureen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication

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