Liu Shihui, Crown Devorah, Miller-Randolph Sharmina, Moayeri Mahtab, Wang Hailun, Hu Haijing, Morley Thomas, Leppla Stephen H
Bacterial Toxins and Therapeutics Section, Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12424-9. doi: 10.1073/pnas.0905409106. Epub 2009 Jul 15.
Anthrax toxin, a major virulence factor of Bacillus anthracis, gains entry into target cells by binding to either of 2 von Willebrand factor A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis. To explore the roles of TEM8 and CMG2 in normal physiology, as well as in anthrax pathogenesis, we generated TEM8- and CMG2-null mice and TEM8/CMG2 double-null mice by deleting TEM8 and CMG2 transmembrane domains. TEM8 and CMG2 were found to be dispensable for mouse development and life, but both are essential in female reproduction in mice. We found that the lethality of anthrax toxin for mice is mostly mediated by CMG2 and that TEM8 plays only a minor role. This is likely because anthrax toxin has approximately 11-fold higher affinity for CMG2 than for TEM8. Finally, the CMG2-null mice are also shown to be highly resistant to B. anthracis spore infection, attesting to the importance of both anthrax toxin and CMG2 in anthrax infections.
炭疽毒素是炭疽芽孢杆菌的一种主要毒力因子，它通过与两种含血管性血友病因子A结构域的蛋白质（肿瘤内皮标志物8，即TEM8和毛细血管形态发生蛋白2，即CMG2）中的任何一种结合进入靶细胞。TEM8和CMG2在多种组织中的广泛表达表明这两种受体可能在炭疽发病机制中发挥作用。为了探究TEM8和CMG2在正常生理以及炭疽发病机制中的作用，我们通过删除TEM8和CMG2的跨膜结构域构建了TEM8基因敲除小鼠、CMG2基因敲除小鼠以及TEM8/CMG2双基因敲除小鼠。我们发现TEM8和CMG2对小鼠的发育和生存并非必需，但二者对小鼠的雌性生殖至关重要。我们发现炭疽毒素对小鼠的致死性主要由CMG2介导，而TEM8仅起次要作用。这可能是因为炭疽毒素对CMG2的亲和力比对TEM8高约11倍。最后，CMG2基因敲除小鼠对炭疽芽孢杆菌孢子感染也表现出高度抗性，这证明了炭疽毒素和CMG2在炭疽感染中的重要性。
