Stabilization of cooperative virulence by the expression of an avirulent phenotype

摘要

Martin Ackermann及其同事将数学模拟与实验rn相结合发现，小肠病原体“鼠伤寒沙门氏菌”rn存遗传上相同的病毒菌群和非病毒菌群是毒性rn在演化上具有稳定性所必需的。喜欢该病原体rn而不喜欢其竞争对手的宿主所发生的炎症来自rn该病原体的合作行为。病毒菌群诱导炎症，非rn病毒菌群限制宿主内非病毒突变体(后者利用rn炎症而不对其做贡献)的生长。这些发现揭示rn了用来打击病原体的一个尚未被发挥的潜力：rn它们意味着，无毒突变体(变节者)保护宿主不rn受有毒菌种的长期感染，并且还可帮助降低传rn播的风险。因此，人为施用有“变节”行为的rn菌种，有可能为控制不需要传统抗生素的感染rn提供个新策略。%Pathogens often infect hosts through collective actions: they secrete growth-promoting compounds or virulence factors, or evoke host reactions that fuel the colonization of the host. Such behaviours are vulnerable to the rise of mutants that benefit from the collective action without contributing to it; how these behaviours can be evo-lutionarily stable is not well understood. We address this question using the intestinal pathogen Salmonella enterica serovar Typhi-murium (hereafter termed S. typhimurium), which manipulates its host to induce inflammation, and thereby outcompetes the commensal microbiota. Notably, the virulence factors needed for host manipulation are expressed in a bistable fashion, leading to a slow-growing subpopulation that expresses virulence genes, and a fast-growing subpopulation that is phenotypically avirulent. Here we show that the expression of the genetically identical but phenotypically avirulent subpopulation is essential for the evolutionary stability of virulence in this pathogen. Using a combination of mathematical modelling, experimental evolution and competition experiments we found that within-host evolution leads to the emergence of mutants that are genetically avirulent and fast-growing. These mutants are defectors that exploit inflammation without contributing to it. In infection experiments initiated with wild-type S. typhimurium, defectors increase only slowly in frequency. In a genetically modified S. typhimurium strain in which the phenotypically avirulent subpopulation is reduced in size, defectors rise more rapidly, inflammation ceases prematurely, and S. typhimurium is quickly cleared from the gut. Our results establish that host manipulation by S. typhimurium is a cooperative trait that is vulnerable to the rise of avirulent defectors; the expression of a phenotypicaDy avirulent subpopulation that grows as fast as defectors slows down this process, and thereby promotes the evolutionary stability of virulence. This points to a key role of bistable virulence gene expression in stabilizing cooperative virulence and may lead the way to new approaches for controlling pathogens.