title: Deciphering tissue-induced Klebsiella pneumoniae lipid A structure.
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.
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Enrique
authors.initials: E
authors.lastname: Llobet
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Verónica
authors.initials: V
authors.lastname: Martínez-Moliner
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Moranta
authors.affiliation: Structural Bioinformatics Laboratory, Department of Biosciences, Åbo Akademi University, FIN-20520 Turku, Finland;
authors.forename: Käthe M
authors.initials: KM
authors.lastname: Dahlström
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Verónica
authors.initials: V
authors.lastname: Regueiro
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Anna
authors.initials: A
authors.lastname: Tomás
authors.affiliation: Department of Microbial Pathogenesis, Institut d'Investigació Sanitària de Palma, 07120 Palma, Spain; Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Victoria
authors.initials: V
authors.lastname: Cano
authors.affiliation: Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, 07210 Bunyola, Spain; Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain;
authors.forename: Camino
authors.initials: C
authors.lastname: Pérez-Gutiérrez
authors.affiliation: Centre for Infection and Immunity, Queen's University, BT9 7AE Belfast, United Kingdom;
authors.forename: Christian G
authors.initials: CG
authors.lastname: Frank
authors.affiliation: Centre for Infection and Immunity, Queen's University, BT9 7AE Belfast, United Kingdom;
authors.forename: Helena
authors.initials: H
authors.lastname: Fernández-Carrasco
authors.affiliation: Centre for Infection and Immunity, Queen's University, BT9 7AE Belfast, United Kingdom;
authors.forename: José Luis
authors.initials: JL
authors.lastname: Insua
authors.affiliation: Structural Bioinformatics Laboratory, Department of Biosciences, Åbo Akademi University, FIN-20520 Turku, Finland;
authors.forename: Tiina A
authors.initials: TA
authors.lastname: Salminen
authors.affiliation: Centro de Investigación Biomédica en Red Enfermedades Respiratorias, 028029 Madrid, Spain; Instituto de Agrobiotecnología, Consejo Superior de Investigaciones Científicas-Universidad Pública de Navarra-Gobierno de Navarra, 31192 Navarra, Spain;
authors.forename: Junkal
authors.initials: J
authors.lastname: Garmendia
authors.affiliation: Centre for Infection and Immunity, Queen's University, BT9 7AE Belfast, United Kingdom; Consejo Superior de Investigaciones Científicas, 28006 Madrid, Spain j.bengoechea@qub.ac.uk.
authors.forename: José A
authors.initials: JA
authors.lastname: Bengoechea
mesh_terms: D000818:Animals; D006801:Humans; D007710:Klebsiella Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000235:genetics / Q000378:metabolism*; D008050:Lipid A / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics; D008168:Lung / Q000382:microbiology; D051379:Mice; D015394:Molecular Structure; D009928:Organ Specificity
chemical_list: D008050:Lipid A
keywords: Klebsiella; LpxO; PhoPQ; colistin; lipid A