Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Llobet E, Martínez-Moliner V, Moranta D, Dahlström KM, Regueiro V, Tomás A, Cano V, Pérez-Gutiérrez C, Frank CG, Fernández-Carrasco H, Insua JL, Salminen TA, Garmendia J, Bengoechea JA
Publisher: National Academy of Sciences
Publication year: 2015
Journal: Proceedings of the National Academy of Sciences
Volume number: 112
Issue number: 46
Start page: E6369
End page: E6378
eISSN: 1091-6490


Abstract

The 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-hydroxyacyl-modified 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 multidrug-resistant 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.


Keywords

colistin, Klebsiella, lipid A, LpxO, PhoPQ

Last updated on 2019-19-07 at 06:34