Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States.
Front Immunol. 2022 May 27;13:886733. doi: 10.3389/fimmu.2022.886733. eCollection 2022.
Pathogens that traffic in the blood of their hosts must employ mechanisms to evade the host innate immune system, including the complement cascade. The Lyme disease spirochete, , has evolved numerous outer membrane lipoproteins that interact directly with host proteins. Compared to Lyme disease-associated spirochetes, relatively little is known about how an emerging tick-borne spirochetal pathogen, , utilizes surface lipoproteins to interact with a human host. expresses the multifunctional lipoprotein, BBK32, that inhibits the classical pathway of complement through interaction with the initiating protease C1r, and also interacts with fibronectin using a separate intrinsically disordered domain. encodes two separate orthologs denoted and ; however, the activities of these proteins are unknown. Here, we show that FbpA binds human fibronectin in a manner similar to BBK32, whereas FbpB does not. FbpA and FbpB both bind human complement C1r and protect a serum-sensitive strain from complement-mediated killing, but surprisingly, differ in their ability to recognize activated C1r versus zymogen states of C1r. To better understand the observed differences in C1r recognition and inhibition properties, high-resolution X-ray crystallography structures were solved of the C1r-binding regions of FbpA and FbpB at 1.9Å and 2.1Å, respectively. Collectively, these data suggest that FbpA and FbpB have partially overlapping functions but are functionally and structurally distinct. The data presented herein enhances our overall understanding of how bloodborne pathogens interact with fibronectin and modulate the complement system.
病原体在宿主血液中传播时，必须采用机制来逃避宿主固有免疫系统，包括补体级联反应。莱姆病螺旋体 ， 已经进化出许多直接与宿主蛋白相互作用的外膜脂蛋白。与莱姆病相关的螺旋体相比，人们对新兴的蜱传螺旋体病原体 ， 如何利用表面脂蛋白与人类宿主相互作用知之甚少。 表达多功能脂蛋白 BBK32，通过与起始蛋白酶 C1r 相互作用抑制补体经典途径，还使用单独的固有无序结构域与纤维连接蛋白相互作用。 编码两个单独的 直系同源物，分别表示为 和 ；然而，这些蛋白质的活性是未知的。在这里，我们表明 FbpA 以类似于 BBK32 的方式与人纤维连接蛋白结合，而 FbpB 则不结合。FbpA 和 FbpB 都与人补体 C1r 结合，并保护对补体介导杀伤敏感的 菌株，但令人惊讶的是，它们识别激活的 C1r 与 C1r 酶原状态的能力不同。为了更好地理解在 C1r 识别和抑制特性方面观察到的差异，我们以 1.9Å 和 2.1Å 的分辨率分别解决了 C1r 结合区的 FbpA 和 FbpB 的高分辨率 X 射线晶体结构。总的来说，这些数据表明 FbpA 和 FbpB 具有部分重叠的功能，但在功能和结构上是不同的。本文所提供的数据增强了我们对血液病原体如何与纤维连接蛋白相互作用并调节补体系统的整体理解。
