Maurelli A T, Fernández R E, Bloch C A, Rode C K, Fasano A
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD 20814-4799, USA.
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3943-8. doi: 10.1073/pnas.95.7.3943.
Plasmids, bacteriophages, and pathogenicity islands are genomic additions that contribute to the evolution of bacterial pathogens. For example, Shigella spp., the causative agents of bacillary dysentery, differ from the closely related commensal Escherichia coli in the presence of a plasmid in Shigella that encodes virulence functions. However, pathogenic bacteria also may lack properties that are characteristic of nonpathogens. Lysine decarboxylase (LDC) activity is present in approximately 90% of E. coli strains but is uniformly absent in Shigella strains. When the gene for LDC, cadA, was introduced into Shigella flexneri 2a, virulence became attenuated, and enterotoxin activity was inhibited greatly. The enterotoxin inhibitor was identified as cadaverine, a product of the reaction catalyzed by LDC. Comparison of the S. flexneri 2a and laboratory E. coli K-12 genomes in the region of cadA revealed a large deletion in Shigella. Representative strains of Shigella spp. and enteroinvasive E. coli displayed similar deletions of cadA. Our results suggest that, as Shigella spp. evolved from E. coli to become pathogens, they not only acquired virulence genes on a plasmid but also shed genes via deletions. The formation of these "black holes," deletions of genes that are detrimental to a pathogenic lifestyle, provides an evolutionary pathway that enables a pathogen to enhance virulence. Furthermore, the demonstration that cadaverine can inhibit enterotoxin activity may lead to more general models about toxin activity or entry into cells and suggests an avenue for antitoxin therapy. Thus, understanding the role of black holes in pathogen evolution may yield clues to new treatments of infectious diseases.
质粒、噬菌体和致病岛是有助于细菌病原体进化的基因组附加成分。例如，志贺氏菌属是细菌性痢疾的病原体，与密切相关的共生大肠杆菌不同，志贺氏菌存在一个编码毒力功能的质粒。然而，病原菌也可能缺乏非病原菌所特有的特性。赖氨酸脱羧酶（LDC）活性在大约90%的大肠杆菌菌株中存在，但在志贺氏菌菌株中则普遍不存在。当将LDC基因cadA导入福氏志贺氏菌2a时，毒力减弱，肠毒素活性受到极大抑制。肠毒素抑制剂被鉴定为尸胺，它是LDC催化反应的产物。比较福氏志贺氏菌2a和实验室大肠杆菌K-12基因组中cadA区域发现，志贺氏菌存在一个大的缺失。志贺氏菌属和侵袭性大肠杆菌的代表性菌株显示出类似的cadA缺失。我们的结果表明，随着志贺氏菌属从大肠杆菌进化为病原体，它们不仅通过质粒获得了毒力基因，还通过缺失失去了一些基因。这些“黑洞”的形成，即对致病生活方式有害的基因缺失，提供了一条进化途径，使病原体能够增强毒力。此外，尸胺能抑制肠毒素活性的证明可能会引出关于毒素活性或进入细胞的更普遍模型，并为抗毒素治疗提供一条途径。因此，了解“黑洞”在病原体进化中的作用可能会为传染病的新治疗方法提供线索。
