Antibiotic Treatment Selects for Cooperative Virulence of Salmonella Typhimurium
Antibiotic Treatment Selects for Cooperative Virulence of Salmonella Typhimurium
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DOI：
10.1016/j.cub.2014.07.028
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发表时间：
2014-09-08
期刊：
影响因子：
9.2
通讯作者：
Hardt, Wolf-Dietrich
中科院分区：
文献类型：
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作者：
Diard, Mederic;Sellin, Mikael E.;Hardt, Wolf-Dietrich
抗生素是一种强大的治疗方法，但对细菌群体中的所有细胞的效果并不相同。表现出抗生素耐受表型（“持续存在”）的细菌可以逃避治疗[1]。持续存在可能导致治疗结束后感染复发[2]。目前尚不清楚持久性是否会影响细菌毒力的进化。在感染过程中，持续存在者优先在宿主体内的特定部位被发现[3, 4]。如果细菌毒力因子需要到达这些位点，那么抗生素治疗除了对细菌耐药性产生明确的影响外，还可以对毒力基因的表达进行选择。在这里，我们报告说，抗生素治疗会选择毒力并促进鼠伤寒沙门氏菌的传播。在沙门氏菌腹泻小鼠模型中，用广谱抗生素环丙沙星治疗可以逆转野生型细菌与宿主进化过程中自发产生的无毒突变体之间的竞争结果[5]。虽然无毒突变体接管了未经治疗的小鼠的肠腔并消除了疾病传播，但环丙沙星却使平衡倾斜，有利于有毒的野生型细菌。这是因为毒力因子需要侵入肠道组织并形成持久的储存库。无毒突变体保留在肠腔中并被根除。抗生素治疗停止后，组织内的野生型病原体会在肠腔中重新播种，从而促进疾病向新宿主的传播。我们的结果提出了一个一般原则，抗生素治疗可以促进宿主内进化过程中的协同毒力，增加传播持续时间，从而增强传染病的传播。
Antibiotics are powerful therapeutics but are not equally effective against all cells in bacterial populations. Bacteria that express an antibiotic-tolerant phenotype ("persisters") can evade treatment [1]. Persisters can cause relapses of the infection after the end of the therapy [2]. It is still poorly understood whether persistence affects the evolution of bacterial virulence. During infections, persisters have been found preferentially at particular sites within the host [3, 4]. If bacterial virulence factors are required to reach such sites, treatment with antibiotics could impose selection on the expression of virulence genes, in addition to their well-established effects on bacterial resistance. Here, we report that treatment with antibiotics selects for virulence and fosters transmissibility of Salmonella Typhimurium. In a mouse model for Salmonella diarrhea, treatment with the broad-spectrum antibiotic ciprofloxacin reverses the outcome of competition between wild-type bacteria and avirulent mutants that can spontaneously arise during within-host evolution [5]. While avirulent mutants take over the gut lumen and abolish disease transmission in untreated mice, ciprofloxacin tilts the balance in favor of virulent, wild-type bacteria. This is explained by the need for virulence factors to invade gut tissues and form a persistent reservoir. Avirulent mutants remain in the gut lumen and are eradicated. Upon cessation of antibiotic treatment, tissue-lodged wild-type pathogens reseed the gut lumen and thereby facilitate disease transmissibility to new hosts. Our results suggest a general principle by which antibiotic treatment can promote cooperative virulence during within-host evolution, increase duration of transmissibility, and thereby enhance the spread of an infectious disease.