Zulianello Laurence, Canard Coralie, Köhler Thilo, Caille Dorothée, Lacroix Jean-Silvain, Meda Paolo
Department of Cell Physiology and Metabolism, Medical Center, University of Geneva, 1, rue Michel Servet, Geneva 04 CH1211, Switzerland.
Infect Immun. 2006 Jun;74(6):3134-47. doi: 10.1128/IAI.01772-05.
The opportunistic bacterium Pseudomonas aeruginosa causes chronic respiratory infections in cystic fibrosis and immunocompromised individuals. Bacterial adherence to the basolateral domain of the host cells and internalization are thought to participate in P. aeruginosa pathogenicity. However, the mechanism by which the pathogen initially modulates the paracellular permeability of polarized respiratory epithelia remains to be understood. To investigate this mechanism, we have searched for virulence factors secreted by P. aeruginosa that affect the structure of human airway epithelium in the early stages of infection. We have found that only bacterial strains secreting rhamnolipids were efficient in modulating the barrier function of an in vitro-reconstituted human respiratory epithelium, irrespective of their release of elastase and lipopolysaccharide. In contrast to previous reports, we document that P. aeruginosa was not internalized by epithelial cells. We further report that purified rhamnolipids, applied on the surfaces of the epithelia, were sufficient to functionally disrupt the epithelia and to promote the paracellular invasion of rhamnolipid-deficient P. aeruginosa. The mechanism involves the incorporation of rhamnolipids within the host cell membrane, leading to tight-junction alterations. The study provides direct evidence for a hitherto unknown mechanism whereby the junction-dependent barrier of the respiratory epithelium is selectively altered by rhamnolipids.
机会致病菌铜绿假单胞菌可在囊性纤维化患者和免疫功能低下个体中引发慢性呼吸道感染。细菌对宿主细胞基底外侧结构域的黏附及内化作用被认为与铜绿假单胞菌的致病性有关。然而，病原体最初调节极化呼吸道上皮细胞旁通透性的机制仍有待明确。为了探究这一机制，我们寻找了铜绿假单胞菌分泌的、在感染早期影响人气道上皮结构的毒力因子。我们发现，只有分泌鼠李糖脂的菌株能够有效调节体外重建的人呼吸道上皮的屏障功能，而不论其弹性蛋白酶和脂多糖的释放情况。与之前的报道不同，我们证明上皮细胞不会内化铜绿假单胞菌。我们进一步报道，将纯化的鼠李糖脂应用于上皮表面，足以在功能上破坏上皮，并促进缺乏鼠李糖脂的铜绿假单胞菌的细胞旁侵袭。其机制包括鼠李糖脂掺入宿主细胞膜，导致紧密连接改变。该研究为一种迄今未知的机制提供了直接证据，即呼吸道上皮依赖连接的屏障被鼠李糖脂选择性改变。
