Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters

By S. Helaine, Angela M. Cheverton, Kathryn G. Watson, Laura M. Faure, S. Matthews, D. Holden. Science, 2014

696 citations recorded by the source corpus.

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. Upon internalization, intracellular Salmonella choose between replication or a form of quiescence known as persistence. 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.

Subfields: Endocrinology, Food Science

View Paper: https://www.semanticscholar.org/paper/26adb6b27d14c4b8b1e4eabe35695db2ff983b28

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Citations in the corpus

Mechanisms of bacterial persistence during stress and antibiotic exposure (2016, background): “coliK-12, single TA module knockouts showed strong defects in persister formation in this model, suggesting that the activity of different TA modules may be linked by some kind of regulatory mechanism (15, 110).”
Antibiotic resistance and persistence—Implications for human health and treatment perspectives (2020, positive): “…including nutrient limitation (Gutierrez et al , 2017), high cell density (Vega et al , 2012), oxidative stress (Wu et al , 2012; Rowe et al , 2020), an acidic environment (Lewis, 2007; Vulin et al , 2018), immune factors (Manina et al , 2015) and exposure to immune cells (Helaine et al , 2014).”
Molecular mechanisms underlying bacterial persisters. (2014, positive): “coli persisters, the Lon-dependent persister induction pathway of Salmonella responded specifically to signals encountered within host cells (Helaine et al., 2014).”
Single-cell RNA-seq: advances and future challenges (2014, positive): “Single-cell studies are also of paramount interest in the clinics, helping to understand how an ‘outlier cell’ may determine the outcome of an infection (2), drug or antibiotic resistance (3,4) and cancer relapse (5).”
Persister formation in Staphylococcus aureus is associated with ATP depletion (2016, positive): “In S. Typhimurium, TA modules are responsible for a sharp increase in persisters when the pathogen infects macrophages 9 .”