2-Hydroxylation of Acinetobacter baumannii Lipid A Contributes to Virulence
2-Hydroxylation of Acinetobacter baumannii Lipid A Contributes to Virulence
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DOI：
10.1128/iai.00066-19
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发表时间：
2019-04-01
影响因子：
3.1
通讯作者：
Bengoechea, Jose A.
中科院分区：
文献类型：
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作者：
Bartholomew, Toby L.;Kidd, Timothy J.;Bengoechea, Jose A.
鲍曼不动杆菌引起广泛的医院感染。这种病原体被认为是对人类健康的威胁，因为越来越频繁地分离出多重耐药菌株。目前对A.鲍曼不动杆菌，并且只有少数毒力因子被表征，包括脂多糖。A.鲍曼不动杆菌是七酰化的并含有2-羟基月桂酸酯。控制脂质A酰化的晚期酰基转移酶已经被表征。在这里，我们报告的表征A。鲍曼不动杆菌LpxO，其编码负责脂质A的2-羟基化的酶。通过遗传学方法和质谱分析，我们证明LpxO催化A.鲍曼不动杆菌LpxO依赖的脂质A2-羟基化保护A.来自多粘菌素B、粘菌素和人β-防御素3的鲍曼不动杆菌。LpxO对A.人全血中的鲍曼不动杆菌，并且是大蜡螟中病原体存活所必需的。LpxO还保护不动杆菌免受G.大蜡螟抗菌肽并限制其表达。进一步证明了LpxO依赖性修饰在免疫逃避中的重要性，脂质A的2-羟基化限制了丝裂原活化蛋白激酶Jun N-末端蛋白激酶的活化以减弱炎症反应。此外，LpxO控制的脂质A修饰通过激活转录因子CREB介导抗炎细胞因子白细胞介素-10（IL-10）的产生。IL-10反过来限制了A.鲍曼不动杆菌感染总之，我们的研究表明，LpxO是一个候选的发展抗A。鲍曼不动杆菌药物。
Acinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasingly frequent isolation of multidrug-resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only a few virulence factors have been characterized, including lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of 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 lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyzes 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 beta-defensin 3. LpxO contributes to the 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 their expression. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of lipid A limits the activation of the mitogen-activated protein kinase Jun N-terminal protein kinase to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine interleukin-10 (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 for the development of anti-A. baumannii drugs.