Institut de Biologie Structurale, UMR 5075 (Comissariat à l'Enérgie Atomique/Centre National de la Recherche Scientifique/Université Grenoble I), Grenoble, France.
PLoS One. 2010 Dec 13;5(12):e15242. doi: 10.1371/journal.pone.0015242.
Yersinia pestis, the causative agent of bubonic plague, employs its type III secretion system to inject toxins into target cells, a crucial step in infection establishment. LcrV is an essential component of the T3SS of Yersinia spp, and is able to associate at the tip of the secretion needle and take part in the translocation of anti-host effector proteins into the eukaryotic cell cytoplasm. Upon cell contact, LcrV is also released into the surrounding medium where it has been shown to block the normal inflammatory response, although details of this mechanism have remained elusive. In this work, we reveal a key aspect of the immunomodulatory function of LcrV by showing that it interacts directly and with nanomolar affinity with the inflammatory cytokine IFNγ. In addition, we generate specific IFNγ mutants that show decreased interaction capabilities towards LcrV, enabling us to map the interaction region to two basic C-terminal clusters of IFNγ. Lastly, we show that the LcrV-IFNγ interaction can be disrupted by a number of inhibitors, some of which display nanomolar affinity. This study thus not only identifies novel potential inhibitors that could be developed for the control of Yersinia-induced infection, but also highlights the diversity of the strategies used by Y. pestis to evade the immune system, with the hijacking of pleiotropic cytokines being a long-range mechanism that potentially plays a key role in the severity of plague.
鼠疫耶尔森菌是引起腺鼠疫的病原体，它利用其三型分泌系统将毒素注入靶细胞，这是感染建立的关键步骤。LcrV 是耶尔森氏菌 T3SS 的一个必需组成部分，能够在分泌针的尖端结合，并参与将抗宿主效应蛋白易位到真核细胞质中。在细胞接触后，LcrV 也会被释放到周围介质中，在那里已经表明它可以阻止正常的炎症反应，尽管这个机制的细节仍然难以捉摸。在这项工作中，我们通过显示 LcrV 直接与具有纳摩尔亲和力的炎症细胞因子 IFNγ相互作用，揭示了 LcrV 免疫调节功能的一个关键方面。此外，我们生成了具有降低与 LcrV 相互作用能力的特定 IFNγ 突变体，使我们能够将相互作用区域映射到 IFNγ 的两个基本 C 末端簇上。最后，我们表明 LcrV-IFNγ 相互作用可以被多种抑制剂破坏，其中一些抑制剂具有纳摩尔亲和力。因此，这项研究不仅确定了一些新的潜在抑制剂，这些抑制剂可能被开发用于控制由耶尔森氏菌引起的感染，还强调了鼠疫耶尔森氏菌逃避免疫系统的策略的多样性，劫持多效细胞因子是一种远程机制，可能在鼠疫的严重程度中发挥关键作用。
