Department of Biochemistry & Molecular Biology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Division of Infectious Diseases, New York State Department of Health, Wadsworth Center, Albany, New York, United States of America.
PLoS Pathog. 2022 May 23;18(5):e1010511. doi: 10.1371/journal.ppat.1010511. eCollection 2022 May.
Hematogenous dissemination is a critical step in the evolution of local infection to systemic disease. The Lyme disease (LD) spirochete, which efficiently disseminates to multiple tissues, has provided a model for this process, in particular for the key early event of pathogen adhesion to the host vasculature. This occurs under shear force mediated by interactions between bacterial adhesins and mammalian cell-surface proteins or extracellular matrix (ECM). Using real-time intravital imaging of the Lyme spirochete in living mice, we previously identified BBK32 as the first LD spirochetal adhesin demonstrated to mediate early vascular adhesion in a living mouse; however, deletion of bbk32 resulted in loss of only about half of the early interactions, suggesting the existence of at least one other adhesin (adhesin-X) that promotes early vascular interactions. VlsE, a surface lipoprotein, was identified long ago by its capacity to undergo rapid antigenic variation, is upregulated in the mammalian host and required for persistent infection in immunocompetent mice. In immunodeficient mice, VlsE shares functional overlap with OspC, a multi-functional protein that displays dermatan sulfate-binding activity and is required for joint invasion and colonization. In this research, using biochemical and genetic approaches as well as intravital imaging, we have identified VlsE as adhesin-X; it is a dermatan sulfate (DS) adhesin that efficiently promotes transient adhesion to the microvasculature under shear force via its DS binding pocket. Intravenous inoculation of mice with a low-passage infectious B. burgdorferi strain lacking both bbk32 and vlsE almost completely eliminated transient microvascular interactions. Comparative analysis of binding parameters of VlsE, BBK32 and OspC provides a possible explanation why these three DS adhesins display different functionality in terms of their ability to promote early microvascular interactions.
血源播散是局部感染发展为全身疾病的关键步骤。伯氏疏螺旋体（Borrelia burgdorferi）能够高效地播散到多种组织，为这一过程提供了一个模型，特别是为病原体与宿主血管黏附这一关键的早期事件提供了模型。这一过程发生在细菌黏附素与哺乳动物细胞表面蛋白或细胞外基质（ECM）之间相互作用介导的切变力下。我们以前曾使用活体小鼠中的实时活体成像技术，对莱姆螺旋体进行研究，鉴定出 BBK32 是第一个被证明可介导活体小鼠早期血管黏附的莱姆螺旋体黏附素；然而，bbk32 的缺失仅导致大约一半的早期相互作用丧失，这表明至少存在另一种黏附素（黏附素-X）促进早期血管相互作用。VlsE 是一种表面脂蛋白，很久以前就因其快速抗原变异的能力而被识别出来，在哺乳动物宿主中上调，并在免疫功能正常的小鼠中持续感染中发挥作用。在免疫缺陷小鼠中，VlsE 与 OspC 具有功能重叠，OspC 是一种多功能蛋白，具有透明质酸结合活性，是关节侵袭和定植所必需的。在这项研究中，我们使用生化和遗传方法以及活体成像，鉴定出 VlsE 是黏附素-X；它是一种透明质酸（DS）黏附素，通过其 DS 结合口袋，在切变力下有效地促进对微脉管的短暂黏附。用缺乏 bbk32 和 vlsE 的低传代传染性 B. burgdorferi 菌株静脉接种小鼠，几乎完全消除了短暂的微血管相互作用。VlsE、BBK32 和 OspC 的结合参数比较分析为这三个 DS 黏附素在促进早期微血管相互作用的能力方面表现出不同的功能提供了一个可能的解释。
