首页|Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death
Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death
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Bacillus anthracis lethal toxin(LT)is a determinant of lethal anthrax.Its function in myeloid cells is required for bacte-rial 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-α)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 epithe-lial 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.
lethal toxinTNFp38αintestinal epithelial cellcell death
State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen 361102,China
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
Laboratory Animal Center,Faculty of Medicine and Life Sciences,Xiamen University,Xiamen 361102,China
National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key R&D Program of ChinaCAMS Innovation Fund for Medical Sciences(CIFMS)Fujian Province Central to Local Science and Technology Development Special ProgramFu-Xia-Quan Zi-Chuang District Cooperation Program
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