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Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters

Science  10 Jan 2014:
Vol. 343, Issue 6167, pp. 204-208
DOI: 10.1126/science.1244705

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Persistent Survival

The role of persister cells—dormant cells that survive multidrug treatment—in the context of bacterial pathogenesis has not been explored in depth. Using a single-cell fluorescent dilution technique, Helaine et al. (p. 204) examined Salmonella Typhimurium persister-cell formation in vitro and in infections in mice. Within 30 min after phagocytosis by macrophages, Salmonella cells follow one of two fates, either to replication and generation of virulence effectors or to remaining viable but become nonreplicating persisters. Salmonella living within a macrophage vacuole are exposed to potentially stressful conditions that induce the expression of 14 Type II toxin-antidote loci in a ppGpp/lon protease-dependent manner, and this system appears to play a role in both virulence factor induction and persister-cell formation. The nonreplicating bacteria represent at least four distinct subpopulations, as defined by their ability to resume growth and their metabolic activity, but different phenotypes are observed in different pathogens and Escherichia coli persisters are distinct from Salmonella persisters.

Abstract

Many bacterial pathogens cause persistent infections despite repeated antibiotic exposure. Bacterial persisters are antibiotic-tolerant cells, but little is known about their growth status and the signals and pathways leading to their formation in infected tissues. We used fluorescent single-cell analysis to identify Salmonella persisters during infection. These were part of a nonreplicating population formed immediately after uptake by macrophages and were induced by vacuolar acidification and nutritional deprivation, conditions that also induce Salmonella virulence gene expression. The majority of 14 toxin-antitoxin modules contributed to intracellular persister formation. Some persisters resumed intracellular growth after phagocytosis by naïve macrophages. Thus, the vacuolar environment induces phenotypic heterogeneity, leading to either bacterial replication or the formation of nonreplicating persisters that could provide a reservoir for relapsing infection.

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