Clostridium species are a group of Gram-positive bacteria that cause diseases in humans, such as food poisoning, botulism, and tetanus. Here, we analyzed 10 different Clostridium species and identified that Clostridium septicum, a pathogen that causes sepsis and gas gangrene, activates the mammalian cytosolic inflammasome complex in mice and humans. Mechanistically, we demonstrate that α-toxin secreted by C. septicum binds to glycosylphosphatidylinositol (GPI)-anchored proteins on the host plasma membrane, oligomerizing and forming a membrane pore that is permissive to efflux of magnesium and potassium ions. Efflux of these cytosolic ions triggers the activation of the innate immune sensor NLRP3, inducing activation of caspase-1 and gasdermin D, secretion of the proinflammatory cytokines interleukin-1β and interleukin-18, pyroptosis, and plasma membrane rupture via ninjurin-1. Furthermore, α-toxin of C. septicum induces rapid inflammasome-mediated lethality in mice and pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents C. septicum-induced lethality. Overall, our results reveal that cytosolic innate sensing of α-toxin is central to the recognition of C. septicum infection and that therapeutic blockade of the inflammasome pathway may prevent sepsis and death caused by toxin-producing pathogens.

中文翻译：

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Clostridium septicum α-毒素通过接合 GPI 锚定蛋白激活 NLRP3 炎性体。

梭状芽胞杆菌属是一组革兰氏阳性细菌，可导致人类疾病，如食物中毒、肉毒杆菌中毒和破伤风。在这里，我们分析了 10 种不同的梭菌，发现败血症梭菌是一种导致败血症和气性坏疽的病原体，可激活小鼠和人类的哺乳动物细胞溶质炎性体复合物。从机理上讲，我们证明了由脓毒杆菌分泌的 α-毒素与宿主质膜上的糖基磷脂酰肌醇 (GPI) 锚定蛋白结合，寡聚化并形成允许镁和钾离子流出的膜孔。这些细胞溶质离子的流出触发先天免疫传感器 NLRP3 的激活，诱导 caspase-1 和 gasdermin D 的激活，促炎细胞因子白细胞介素 1β 和白细胞介素 18 的分泌，细胞焦亡，和通过ninjurin-1的质膜破裂。此外，脓毒性梭菌的 α 毒素在小鼠中诱导快速炎症小体介导的致死性，并且使用 MCC950 对 NLRP3 炎症小体的药理抑制可防止脓毒性梭状芽孢杆菌诱导的致死性。总体而言，我们的研究结果表明，α-毒素的细胞溶质先天感知对于识别脓毒症感染至关重要，炎症小体通路的治疗性阻断可以预防产毒素病原体引起的败血症和死亡。