Black W J, Munoz J J, Peacock M G, Schad P A, Cowell J L, Burchall J J, Lim M, Kent A, Steinman L, Falkow S
Department of Medical Microbiology, Stanford University, CA 94305.
Science. 1988 Apr 29;240(4852):656-9. doi: 10.1126/science.2896387.
Pertussis toxin is produced by the causative agent of whooping cough, Bordetella pertussis, and is an adenosine diphosphate (ADP)-ribosyltransferase capable of covalently modifying and thereby inactivating many eukaryotic G proteins involved in cellular metabolism. The toxin is a principal determinant of virulence in whooping cough and is a primary candidate for an acellular pertussis vaccine, yet it is unclear whether the ADP-ribosyltransferase activity is required for both pathogenic and immunoprotective activities. A B. pertussis strain that produced an assembled pertussis holotoxin with only 1 percent of the ADP-ribosyltransferase activity of the native toxin was constructed and was found to be deficient in pathogenic activities associated with B. pertussis including induction of leukocytosis, potentiation of anaphylaxis, and stimulation of histamine sensitivity. Moreover, this mutant strain failed to function as an adjuvant and was less effective in protecting mice from intracerebral challenge infection. These data suggest that the ADP-ribosyltransferase activity is necessary for both pathogenicity and optimum immunoprotection. These findings bear directly on the design of a nontoxic pertussis vaccine.
百日咳毒素由百日咳的病原体百日咳博德特氏菌产生，是一种二磷酸腺苷（ADP）核糖基转移酶，能够共价修饰并因此使许多参与细胞代谢的真核G蛋白失活。该毒素是百日咳毒力的主要决定因素，也是无细胞百日咳疫苗的主要候选物，但尚不清楚ADP核糖基转移酶活性对于致病和免疫保护活性是否都是必需的。构建了一种产生组装型百日咳全毒素的百日咳博德特氏菌菌株，其ADP核糖基转移酶活性仅为天然毒素的1%，结果发现该菌株在与百日咳博德特氏菌相关的致病活性方面存在缺陷，包括诱导白细胞增多、增强过敏反应以及刺激组胺敏感性。此外，这种突变菌株不能作为佐剂发挥作用，在保护小鼠免受脑内攻击感染方面效果较差。这些数据表明，ADP核糖基转移酶活性对于致病性和最佳免疫保护都是必需的。这些发现直接关系到无毒百日咳疫苗的设计。
