Department of Medical Microbiology, School of Biology & Basic Medical Sciences, Medical College of Soochow University, Suzhou, Jiangsu, PR China.
Gut Microbes. 2021 Jan-Dec;13(1):1-18. doi: 10.1080/19490976.2020.1849996.
Iron withholding, an essential component of nutritional immunity, plays a fundamental role in host resistance to infection. Our previous study showed that SpvB, an important pSLT-encoded cytotoxic effector, facilitated pathogenesis within macrophages via perturbing cellular iron metabolism. However, the underlying mechanisms of SpvB in -relevant disorders of systemic iron metabolism have not yet been identified. Here, we demonstrated that SpvB facilitated to scavenge iron from the host by modulating the hepcidin-ferroportin axis, a key regulator of systemic iron metabolism. We observed that SpvB enhanced hepatic hepcidin synthesis in a STAT3-dependent manner, but not the BMP/SMAD pathway. This subsequently resulted in a reduction of the unique cellular iron exporter ferroportin, which facilitated hypoferremia and hepatic iron accumulation and ultimately countered the limitation of iron availability, thereby improving the chances of survival and replication. Moreover, SpvB promoted the production of proinflammatory molecules associated with the infiltration of inflammatory cells via highly upregulating TREM-1 signaling. Our data supported a role of TREM-1 in SpvB-related dysregulation of host iron metabolism and suggested that targeting TREM-1 might provide a potential therapeutic strategy to prevent or alleviate pathogenesis.
铁剥夺，营养免疫的一个重要组成部分，在宿主抗感染中起着至关重要的作用。我们之前的研究表明，SpvB，一种重要的 pSLT 编码细胞毒性效应物，通过扰乱细胞内铁代谢促进巨噬细胞中的发病机制。然而，SpvB 在与系统铁代谢相关的疾病中的潜在机制尚未确定。在这里，我们证明 SpvB 通过调节铁调素-亚铁转运蛋白轴（系统铁代谢的关键调节剂）促进从宿主中摄取铁。我们观察到 SpvB 以依赖 STAT3 的方式增强肝脏中hepcidin 的合成，但不增强 BMP/SMAD 途径。这随后导致独特的细胞铁输出蛋白 ferroportin 的减少，促进低铁血症和肝脏铁积累，并最终抵消铁可用性的限制，从而提高存活和复制的机会。此外，SpvB 通过高度上调 TREM-1 信号促进与炎症细胞浸润相关的促炎分子的产生。我们的数据支持 TREM-1 在 SpvB 相关宿主铁代谢失调中的作用，并表明靶向 TREM-1 可能提供一种潜在的治疗策略，以预防或减轻发病机制。
