Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: 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
Förläggare: National Academy of Sciences
Publiceringsår: 2015
Tidskrift: Proceedings of the National Academy of Sciences
Volym: 112
Nummer: 46
Artikelns första sida, sidnummer: E6369
Artikelns sista sida, sidnummer: E6378
eISSN: 1091-6490


Abstrakt

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.


Nyckelord

colistin, Klebsiella, lipid A, LpxO, PhoPQ

Senast uppdaterad 2019-17-10 vid 03:48