Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death  

作　　者：Xinhe Gao Teng Teng Yifei Liu Tingting Ai Rui Zhao Yilong Fu Peipei Zhang Jiahuai Han Yingying Zhang 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen 361102,China [2]Research Unit of Cellular Stress of CAMS,Xiang'an Hospital of Xiamen University,Cancer Research Center of Xiamen University,School of Medicine,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen 361102,China [3]Laboratory Animal Center,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen 361102,China

出　　处：《Protein & Cell》2024年第2期135-148,共14页蛋白质与细胞（英文版）

基　　金：supported by the National Natural Science Foundation of China (grant 82388201 to J.H.,grant 31701205 to P.Z.,grant 31801158 to Y.z.);the National Key R&D Program of China (2020YFA0803500 to J.H.);the CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-062 to J.H.);the Fujian Province Central to Local Science and Technology Development Special Program (2022L3079 to J.H.);the Fu-Xia-Quan Zi-Chuang District Cooperation Program (3502ZCQXT2022003 to J.H.).

摘　　要：Bacillus 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-a(TNF-a)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 p38a 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,p38a 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.

关 键 词：lethal toxin TNF p38a intestinal epithelial cell cell death 

分 类 号：R574[医药卫生—消化系统]