Bacillus anthracis (B. anthracis) lethal toxin (LT) is a determinant of lethal anthrax. Its function in myeloid cells is required for bacterial dissemination, and LT itself can directly trigger dysfunction of the cardiovascular system. The interplay between LT and the host responses is important in the pathogenesis, but our knowledge on this interplay remains limited. Tumor necrosis factor-α (TNF) is a pleiotropic pro-inflammatory cytokine induced by bacterial infections. Since LT accumulates and cytokines, predominantly TNF, amass during B. anthracis infection, co-treatment of TNF+LT in mice was used to mimic in vivo conditions for LT to function in inflamed hosts. Bone marrow transplantation and genetically engineered mice showed unexpectedly that the death of intestinal epithelial cells (IECs) rather than that of hematopoietic cells led to LT+TNF-induced lethality. Inhibition of p38α mitogen-activated protein kinase (MAPK) signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs, leading to intestinal damage and mouse death. Consistently, p38α inhibition by LT enhanced TNF-mediated cell death in human colon epithelial HT-29 cells. As intestinal damage is one of the leading causes of lethality in anthrax patients, the IEC damage caused by LT+TNF would most likely be a mechanism underneath this clinical manifestation and could be a target for interventions.

中文翻译：

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炭疽致死毒素和肿瘤坏死因子-α 协同作用于肠上皮，诱导小鼠死亡。

炭疽杆菌（B. anthracis）致死毒素（LT）是致死性炭疽的决定因素。它在骨髓细胞中的功能是细菌传播所必需的，LT 本身可以直接引发心血管系统功能障碍。LT 和宿主反应之间的相互作用在发病机制中很重要，但我们对这种相互作用的了解仍然有限。肿瘤坏死因子-α (TNF) 是一种由细菌感染诱导的多效性促炎细胞因子。由于炭疽杆菌感染期间 LT 会积累，并且细胞因子（主要是 TNF）会积聚，因此在小鼠中使用 TNF+LT 共同治疗来模拟 LT 在发炎宿主中发挥作用的体内条件。骨髓移植和基因工程小鼠出乎意料地表明，肠上皮细胞（IEC）而不是造血细胞的死亡导致了LT+TNF诱导的致死。LT 对 IEC 中 p38α 丝裂原激活蛋白激酶 (MAPK) 信号的抑制促进了 TNF 诱导的 IEC 细胞凋亡和坏死性凋亡，导致肠道损伤和小鼠死亡。一致地，LT 抑制 p38α 增强了人结肠上皮 HT-29 细胞中 TNF 介导的细胞死亡。由于肠道损伤是炭疽患者死亡的主要原因之一，因此 LT+TNF 引起的 IEC 损伤很可能是这种临床表现背后的机制，并且可能成为干预的目标。