Bacteria elevate extracellular adenosine to exploit host signaling for blood-brain barrier disruption

Bacterial meningitis remains a substantial cause of mortality worldwide and survivors may have severe lifelong disability. Although we know that meningeal bacterial pathogens must cross blood-central nervous system (CNS) barriers, the mechanisms which facilitate the virulence of these pathogens are poorly understood. Here, we show that adenosine from a surface enzyme (Ssads) of <i>Streptococcus suis</i> facilitates this pathogen’s entry into mouse brains. Monolayer translocation assays (from the human cerebrovascular endothelium) and experiments using diverse inhibitors and agonists together demonstrate that activation of the A1 adenosine receptor signaling cascade in hosts, as well as attendant cytoskeleton remodeling, promote <i>S. suis</i> penetration across blood-CNS barriers. Importantly, our additional findings showing that Ssads orthologs from other bacterial species also promote their translocation across barriers suggest that exploitation of A1 AR signaling may be a general mechanism of bacterial virulence.

细菌性脑膜炎仍是全球范围内导致死亡的重大病因，存活者往往会遗留严重的终身残疾。尽管已知脑膜致病菌必须跨越血-中枢神经系统（blood-central nervous system, CNS）屏障，但调控这些致病菌致病力的具体机制仍知之甚少。本研究证实，猪链球菌（Streptococcus suis）表面酶Ssads所产生的腺苷，可促进该致病菌侵入小鼠脑组织。通过基于人类脑血管内皮细胞的单层屏障移位实验，以及使用多种抑制剂与激动剂开展的相关实验，结果共同证明：宿主体内A1腺苷受体（A1 adenosine receptor, A1 AR）信号级联反应的激活，伴随相应的细胞骨架重塑，可促进猪链球菌跨越血-中枢神经系统屏障。值得注意的是，我们的额外研究结果显示，其他细菌的Ssads直系同源物同样可促进自身跨越屏障移位，这表明利用A1 AR信号通路或许是细菌致病的通用机制。