sublethal doses of anthrax lethal toxin on the suppression of macrophage phagocytosis亚致死剂量的炭疽致命毒素抑制巨噬细胞的吞噬作用.pdf

Sublethal Doses of Anthrax Lethal Toxin on the Suppression of Macrophage Phagocytosis 1. 2. 2 2 1 Jyh-Hwa Kau , Der-Shan Sun , Hsuan-Shun Huang , Te-Sheng Lien , Hsin-Hsien Huang , Hung-Chi 1 2 Lin , Hsin-Hou Chang * 1 Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China, 2 Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan, Republic of China Abstract Background: Lethal toxin (LT), the major virulence factor produced by Bacillus anthracis, has been shown to suppress the immune system, which is beneficial to the establishment of B. anthracis infections. It has been suggested that the suppression of MEK/MAPK signaling pathways of leukocytes contributes to LT-mediated immunosuppressive effects. However, the involvement of MAPK independent pathways has not been clearly elucidated; nor has the crucial role played by LT in the early stages of infection. Determining whether LT exerts any pathological effects before being enriched to an MEK inhibitory level is an important next step in the furtherance of this field. Methodology/Principal Findings: Using a cell culture model, we determined that low doses of LT inhibited phagocytosis of macrophages, without influencing MAPK pathways. Consistent low doses of LT significantly suppressed bacterial clearance and enhanced the mortality of mice with bacteremia, without suppressing the MEK1 of splenic and peripheral blood mononuclear cells. Conclusion/Significance: These results suggest that LT suppresses the phagocytes in a dose range lower than that required to suppress MEK1 in the early