Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agricultural, Food & Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
Unité Micalis, Domaine de La Minière, Unité Mixte de Recherche 1319, Institut National de la Recherche Agronomique, 78280 Guyancourt, France.
Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2301045120. doi: 10.1073/pnas.2301045120. Epub 2023 Aug 22.
Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogen (Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell-cell signaling peptide PapR regulate virulence gene expression in response to fluctuations in population density, i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to affect the host immune system. Here, we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins similarly to the profile that was observed for isogenic strains. Our findings provide evidence that Bc infectivity is regulated by QS circuit-mediated destruction of host immunity, thus reveal a interesting strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes a readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.
对于任何给定的病原体来说，颠覆宿主免疫系统是其保证生存和增殖的主要任务。对于机会性人类病原体（Bc）来说，免疫逃避使其能够建立强有力的感染。在 Bc 群的各种物种中，多效调节因子 PlcR 和其同源细胞间信号肽 PapR 响应群体密度波动调节毒力基因表达，即群体感应（QS）系统。然而，QS 如何在感染过程中发挥作用，以及 PlcR 是否赋予免疫逃避能力仍不清楚。本文报道了 Bc 中 QS 通讯的阻断如何消除影响宿主免疫系统的能力。在这里，我们设计了一种基于肽的 QS 抑制剂，该抑制剂可抑制 PlcR 依赖性毒力因子的表达，并在小鼠模型中减弱 Bc 的感染力。我们证明，QS 肽抑制剂通过降低 PlcR 调节的主要毒素的表达来阻断宿主免疫系统介导的清除，类似于观察到的同基因菌株的情况。我们的发现提供了证据表明，QS 电路介导的宿主免疫破坏调节 Bc 的感染力，从而揭示了一种限制 Bc 毒力和增强宿主防御的有趣策略。这种肽类群体感应淬灭剂构成了研究其他病原体 QS 系统如何调节宿主免疫的一种易于获得的化学工具，并为抗感染治疗药物的开发奠定了基础。
