Physiologic Stresses Reveal a <i>Salmonella</i> Persister State and TA Family Toxins Modulate Tolerance to These Stresses

<div><p>Bacterial persister cells are considered a basis for chronic infections and relapse caused by bacterial pathogens. Persisters are phenotypic variants characterized by low metabolic activity and slow or no replication. This low metabolic state increases pathogen tolerance to antibiotics and host immune defenses that target actively growing cells. In this study we demonstrate that within a population of <i>Salmonella enterica</i> serotype Typhimurium, a small percentage of bacteria are reversibly tolerant to specific stressors that mimic the macrophage host environment. Numerous studies show that Toxin-Antitoxin (TA) systems contribute to persister states, based on toxin inhibition of bacterial metabolism or growth. To identify toxins that may promote a persister state in response to host-associated stressors, we analyzed the six TA loci specific to <i>S</i>. <i>enterica</i> serotypes that cause systemic infection in mammals, including five RelBE family members and one VapBC member. Deletion of TA loci increased or decreased tolerance depending on the stress conditions. Similarly, exogenous expression of toxins had mixed effects on bacterial survival in response to stress. In macrophages, <i>S</i>. Typhimurium induced expression of three of the toxins examined. These observations indicate that distinct toxin family members have protective capabilities for specific stressors but also suggest that TA loci have both positive and negative effects on tolerance.</p>