Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection.
Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection.
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DOI：
10.1371/journal.pone.0008439
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发表时间：
2009-12-23
期刊：
影响因子：
3.7
通讯作者：
Bragonzi A
中科院分区：
文献类型：
--
作者：
Cigana C;Curcurù L;Leone MR;Ieranò T;Lorè NI;Bianconi I;Silipo A;Cozzolino F;Lanzetta R;Molinaro A;Bernardini ML;Bragonzi A
铜绿假单胞菌可在囊性纤维化 (CF) 患者中建立终生气道慢性感染，其致病变异与最初获得的菌株不同。在这里，我们分析了克隆菌株（包括粘液样和非粘液表型）中铜绿假单胞菌病原体相关分子模式（PAMP）的化学和生物活性，这些克隆菌株是在长达 7.5 年的时间内从 CF 患者中分离出来的。通过 MS 光谱分析确定了脂多糖 (LPS) 脂质 A 和肽聚糖 (PGN) 胞肽的化学结构，这些肽具有与 CF 肺部感染暂时相关的特定结构修饰。基因序列分析揭示了 pagL 中的新突变，该突变支持脂质 A 的变化。 LPS 和 PGN 通过结合 TLR4 和 Nod1 激活宿主先天免疫时具有不同的效力。与晚期菌株相比，分别用从早期铜绿假单胞菌菌株纯化的 LPS 和 PGN 刺激后，在 HEK293hTLR4/MD2-CD14 和 HEK293hNod1 中检测到显着更高的 NF-kB 激活、IL-8 表达和产量。在巨噬细胞样细胞 THP-1、CF 来源的上皮细胞 IB3-1 及其同基因细胞 C38 中获得了类似的结果，通过插入囊性纤维化跨膜电导调节器 (CFTR) 进行校正。在小鼠模型中，与早期菌株相比，铜绿假单胞菌晚期菌株 LPS 结构的改变导致支气管肺泡灌洗液中白细胞募集降低，肺匀浆中 MIP-2、KC 和 IL-1β 细胞因子水平降低。肺组织切片的组织病理学分析证实了早期和晚期铜绿假单胞菌LPS之间的差异。最后，在这项研究中，我们首次揭示了铜绿假单胞菌如何进化出逃避免疫系统检测的能力，从而促进生存并为长期持续存在创造有利条件。我们的研究结果提供了有关 CF 慢性感染的相关信息。
Pseudomonas aeruginosa can establish life-long airways chronic infection in patients with cystic fibrosis (CF) with pathogenic variants distinguished from initially acquired strain. Here, we analysed chemical and biological activity of P. aeruginosa Pathogen-Associated Molecular Patterns (PAMPs) in clonal strains, including mucoid and non-mucoid phenotypes, isolated during a period of up to 7.5 years from a CF patient. Chemical structure by MS spectrometry defined lipopolysaccharide (LPS) lipid A and peptidoglycan (PGN) muropeptides with specific structural modifications temporally associated with CF lung infection. Gene sequence analysis revealed novel mutation in pagL, which supported lipid A changes. Both LPS and PGN had different potencies when activating host innate immunity via binding TLR4 and Nod1. Significantly higher NF-kB activation, IL-8 expression and production were detected in HEK293hTLR4/MD2-CD14 and HEK293hNod1 after stimulation with LPS and PGN respectively, purified from early P. aeruginosa strain as compared to late strains. Similar results were obtained in macrophages-like cells THP-1, epithelial cells of CF origin IB3-1 and their isogenic cells C38, corrected by insertion of cystic fibrosis transmembrane conductance regulator (CFTR). In murine model, altered LPS structure of P. aeruginosa late strains induces lower leukocyte recruitment in bronchoalveolar lavage and MIP-2, KC and IL-1β cytokine levels in lung homogenates when compared with early strain. Histopathological analysis of lung tissue sections confirmed differences between LPS from early and late P. aeruginosa. Finally, in this study for the first time we unveil how P. aeruginosa has evolved the capacity to evade immune system detection, thus promoting survival and establishing favourable conditions for chronic persistence. Our findings provide relevant information with respect to chronic infections in CF.
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DOI：
10.1016/j.bbrc.2006.09.132
发表时间：
2006-12-01
影响因子：
3.1
作者：
Cigana, Cristina;Nicolis, Elena;Melotti, Paola
通讯作者：
Melotti, Paola
影响因子：
56.9
作者：
Ernst, RK;Yi, EC;Miller, SI
通讯作者：
Miller, SI
影响因子：
64.8
作者：
EGAN, M;FLOTTE, T;GUGGINO, WB
通讯作者：
GUGGINO, WB
影响因子：
6.4
作者：
Ernst, Robert K.;Moskowitz, Samuel M.;Miller, Samuel I.
通讯作者：
Miller, Samuel I.
影响因子：
4.8
作者：
Girardin, SE;Travassos, LH;Mengin-Lecreulx, D
通讯作者：
Mengin-Lecreulx, D