Selection for phage resistance reduces virulence of Shigella flexneri

There is increasing interest in phage therapy as an alternative to chemical antibiotics for treating bacterial infections, especially using phages that select for evolutionary trade-offs between increased phage resistance and decreased fitness traits such as virulence in target bacteria. A vast repertoire of virulence factors allows the opportunistic bacterial pathogen, Shigella flexneri, to invade human gut epithelial cells, to replicate intracellularly, and to evade host immunity through intercellular spread; the latter is an infection stage that causes tissue damage, contributing to host mortality. It is previously shown that outer membrane porin OmpA of S. flexneri is necessary for polar localization of virulence factor IcsA, which polymerizes host actin and results in bacterial motility within infected cells. We hypothesized that a phage which uses OmpA as a receptor to recognize, bind and infect S. flexneri, should select for phage-resistant mutants with attenuated intercellular s...噬菌体疗法作为治疗细菌性感染的化学抗生素替代策略，正获得日益增长的研究关注；其中尤其受重视的是，这类噬菌体可筛选出目标细菌的进化权衡突变体——即获得噬菌体抗性的同时，其适合度相关性状（如致病力）出现下降。机会性细菌病原体福氏志贺菌（Shigella flexneri）拥有海量的毒力因子库，使其能够侵袭人体肠道上皮细胞、在细胞内增殖，并通过细胞间扩散逃避宿主免疫；这一细胞间扩散的感染阶段会造成组织损伤，进而加剧宿主死亡风险。已有研究证实，福氏志贺菌的外膜孔蛋白OmpA（outer membrane porin OmpA）是毒力因子IcsA极性定位的必需条件；IcsA可聚合宿主肌动蛋白，使细菌在受感染细胞内获得运动能力。我们提出假说：以OmpA作为受体来识别、结合并感染福氏志贺菌的噬菌体，应当会筛选出细胞间扩散能力减弱的噬菌体抗性突变体……