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Title

Deciphering tissue-induced Klebsiella pneumoniae lipid a structure

AuthorsLlobet Brossa, Enrique; Garmendia, Juncal ; Bengoechea, José Antonio
KeywordsPhoPQ
LpxO
Colistin
Klebsiella
Lipid A
Issue Date2015
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences 112(46): E6369-E6378 (2015)
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.
DescriptionLlobet Brossa, Enrique et al.
Publisher version (URL)http://doi.org/10.1073/pnas.1508820112
URIhttp://hdl.handle.net/10261/141205
DOI10.1073/pnas.1508820112
Identifiersissn: 1091-6490
Appears in Collections:(IDAB) Artículos
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