Tufts University School of Medicine, Boston, Massachusetts, USA.
PLoS Negl Trop Dis. 2010 Dec 14;4(12):e918. doi: 10.1371/journal.pntd.0000918.
Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but causes infections in animals and humans in temperate regions as well. The agents of leptospirosis comprise several members of the genus Leptospira, which also includes non-pathogenic, saprophytic species. Leptospirosis can vary in severity from a mild, non-specific illness to severe disease that includes multi-organ failure and widespread endothelial damage and hemorrhage. To begin to investigate how pathogenic leptospires affect endothelial cells, we compared the responses of two endothelial cell lines to infection by pathogenic versus non-pathogenic leptospires. Microarray analyses suggested that pathogenic L. interrogans and non-pathogenic L. biflexa triggered changes in expression of genes whose products are involved in cellular architecture and interactions with the matrix, but that the changes were in opposite directions, with infection by L. biflexa primarily predicted to increase or maintain cell layer integrity, while L. interrogans lead primarily to changes predicted to disrupt cell layer integrity. Neither bacterial strain caused necrosis or apoptosis of the cells even after prolonged incubation. The pathogenic L. interrogans, however, did result in significant disruption of endothelial cell layers as assessed by microscopy and the ability of the bacteria to cross the cell layers. This disruption of endothelial layer integrity was abrogated by addition of the endothelial protective drug lisinopril at physiologically relevant concentrations. These results suggest that, through adhesion of L. interrogans to endothelial cells, the bacteria may disrupt endothelial barrier function, promoting dissemination of the bacteria and contributing to severe disease manifestations. In addition, supplementing antibiotic therapy with lisinopril or derivatives with endothelial protective activities may decrease the severity of leptospirosis.
钩端螺旋体病是一种广泛存在的人畜共患传染病，主要影响热带地区的居民，但也会在温带地区的动物和人类中引起感染。钩端螺旋体病的病原体包括几个钩端螺旋体属的成员，其中也包括非致病性的腐生种。钩端螺旋体病的严重程度可从轻度、非特异性疾病到严重疾病不等，严重疾病包括多器官衰竭和广泛的内皮损伤和出血。为了开始研究致病性钩端螺旋体如何影响内皮细胞，我们比较了两种内皮细胞系对致病性和非致病性钩端螺旋体感染的反应。微阵列分析表明，致病性的问号钩端螺旋体和非致病性的双曲钩端螺旋体触发了其产物参与细胞结构和与基质相互作用的基因表达的变化，但变化方向相反，双曲钩端螺旋体感染主要预测会增加或维持细胞层的完整性，而问号钩端螺旋体主要导致预测会破坏细胞层完整性的变化。即使经过长时间孵育，两种细菌株都没有导致细胞坏死或凋亡。然而，致病性的问号钩端螺旋体确实导致了内皮细胞层的显著破坏，这可以通过显微镜观察和细菌穿过细胞层的能力来评估。用生理相关浓度的内皮保护药物赖诺普利添加可消除内皮层完整性的破坏。这些结果表明，通过问号钩端螺旋体与内皮细胞的粘附，细菌可能破坏内皮屏障功能，促进细菌的传播，并导致严重的疾病表现。此外，在用赖诺普利或具有内皮保护活性的衍生物补充抗生素治疗时，可能会降低钩端螺旋体病的严重程度。
