Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
Nat Microbiol. 2023 Apr;8(4):666-678. doi: 10.1038/s41564-023-01338-6. Epub 2023 Mar 6.
Granulomas are organized immune cell aggregates formed in response to chronic infection or antigen persistence. The bacterial pathogen Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signalling and immune defence, inducing neutrophil-rich pyogranulomas (PGs) within lymphoid tissues. Here we uncover that Yp also triggers PG formation within the murine intestinal mucosa. Mice lacking circulating monocytes fail to form defined PGs, have defects in neutrophil activation and succumb to Yp infection. Yersinia lacking virulence factors that target actin polymerization to block phagocytosis and reactive oxygen burst do not induce PGs, indicating that intestinal PGs form in response to Yp disruption of cytoskeletal dynamics. Notably, mutation of the virulence factor YopH restores PG formation and control of Yp in mice lacking circulating monocytes, demonstrating that monocytes override YopH-dependent blockade of innate immune defence. This work reveals an unappreciated site of Yersinia intestinal invasion and defines host and pathogen drivers of intestinal granuloma formation.
肉芽肿是由慢性感染或抗原持续存在引起的有组织的免疫细胞聚集。细菌病原体假结核耶尔森氏菌（Yp）阻断先天炎症信号和免疫防御，在淋巴组织中诱导富含中性粒细胞的脓性肉芽肿（PGs）。在这里，我们发现 Yp 还会在小鼠的肠道黏膜中引发 PG 的形成。缺乏循环单核细胞的小鼠无法形成明确的 PGs，其中性粒细胞的激活存在缺陷，并易感染 Yp。缺乏针对肌动蛋白聚合以阻断吞噬作用和活性氧爆发的毒力因子的 Yp 不会诱导 PGs 的形成，表明肠道 PGs 是对 Yp 破坏细胞骨架动力学的反应而形成的。值得注意的是，缺失毒力因子 YopH 可恢复循环单核细胞缺乏的小鼠中 PG 的形成和对 Yp 的控制，表明单核细胞可克服 YopH 对先天免疫防御的依赖性阻断。这项工作揭示了耶尔森氏菌肠道侵袭的一个未被认识的部位，并确定了宿主和病原体在肠道肉芽肿形成中的驱动因素。
