2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence

Toby L Bartholomew, Timothy J Kidd, Joana Sá Pessoa, Raquel Conde Álvarez, José A Bengoechea

Research output: Contribution to journalArticle

Abstract

Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasing isolation of multidrug resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only few virulence factors have been characterized including the lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of the lipid A have been already characterized. Here we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of the lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyses the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human β-defensin 3. LpxO contributes to survival of A. baumannii in human whole blood, and is required for pathogen survival in the waxmoth Galleria mellonella LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits the expression of them. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of the lipid A limits the activation of MAPK JNK to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine IL-10 via the activation of the transcriptional factor CREB. IL-10, in turn, limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate to develop anti A. baumannii drugs.

LanguageEnglish
JournalInfection and Immunity
Early online date25 Mar 2019
DOIs
Publication statusEarly online date - 25 Mar 2019

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Acinetobacter baumannii
Lipid A
Hydroxylation
Virulence
Interleukin-10
Acinetobacter Infections
Laurates
Cytokines
Immune Evasion
Colistin
Acyltransferases
Polymyxin B
Acinetobacter
Survival
Acylation
Virulence Factors
Cross Infection
Transcriptional Activation
Lipopolysaccharides
Mass Spectrometry

Cite this

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title = "2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence",
abstract = "Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasing isolation of multidrug resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only few virulence factors have been characterized including the lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of the lipid A have been already characterized. Here we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of the lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyses the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human β-defensin 3. LpxO contributes to survival of A. baumannii in human whole blood, and is required for pathogen survival in the waxmoth Galleria mellonella LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits the expression of them. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of the lipid A limits the activation of MAPK JNK to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine IL-10 via the activation of the transcriptional factor CREB. IL-10, in turn, limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate to develop anti A. baumannii drugs.",
author = "Bartholomew, {Toby L} and Kidd, {Timothy J} and {S{\'a} Pessoa}, Joana and {Conde {\'A}lvarez}, Raquel and Bengoechea, {Jos{\'e} A}",
year = "2019",
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2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence. / Bartholomew, Toby L; Kidd, Timothy J; Sá Pessoa, Joana; Conde Álvarez, Raquel; Bengoechea, José A.

In: Infection and Immunity, 25.03.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 2-hydroxylation of Acinetobacter baumannii lipid A contributes to virulence

AU - Bartholomew, Toby L

AU - Kidd, Timothy J

AU - Sá Pessoa, Joana

AU - Conde Álvarez, Raquel

AU - Bengoechea, José A

PY - 2019/3/25

Y1 - 2019/3/25

N2 - Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasing isolation of multidrug resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only few virulence factors have been characterized including the lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of the lipid A have been already characterized. Here we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of the lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyses the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human β-defensin 3. LpxO contributes to survival of A. baumannii in human whole blood, and is required for pathogen survival in the waxmoth Galleria mellonella LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits the expression of them. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of the lipid A limits the activation of MAPK JNK to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine IL-10 via the activation of the transcriptional factor CREB. IL-10, in turn, limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate to develop anti A. baumannii drugs.

AB - Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasing isolation of multidrug resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only few virulence factors have been characterized including the lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of the lipid A have been already characterized. Here we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of the lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyses the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human β-defensin 3. LpxO contributes to survival of A. baumannii in human whole blood, and is required for pathogen survival in the waxmoth Galleria mellonella LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits the expression of them. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of the lipid A limits the activation of MAPK JNK to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine IL-10 via the activation of the transcriptional factor CREB. IL-10, in turn, limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate to develop anti A. baumannii drugs.

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DO - 10.1128/IAI.00066-19

M3 - Article

JO - Infection and Immunity

T2 - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

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