Deciphering tissue-induced Klebsiella pneumoniae lipid A structure
Fecha
2015Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.1073/pnas.1508820112
Resumen
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 ...
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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-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. [--]
Materias
Lipid A,
Klebsiella,
Colistin,
LpxO,
PhoPQ
Editor
National Academy of Sciences
Publicado en
PNAS November 17, 2015 112 (46) E6369-E6378
Departamento
Universidad Pública de Navarra/Nafarroako Unibertsitate Publikoa. IdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutua
Versión del editor
Entidades Financiadoras
This 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.).