Persistence of Intracellular Bacterial Pathogens-With a Focus on the Metabolic Perspective

Abstract

Persistence has evolved as a potent survival strategy to overcome adverse environmental conditions. This capability is common to almost all bacteria, including all human bacterial pathogens and likely connected to chronic infections caused by some of these pathogens. Although the majority of a bacterial cell population will be killed by the particular stressors, like antibiotics, oxygen and nitrogen radicals, nutrient starvation and others, a varying subpopulation (termed persisters) will withstand the stress situation and will be able to revive once the stress is removed. Several factors and pathways have been identified in the past that apparently favor the formation of persistence, such as various toxin/antitoxin modules or stringent response together with the alarmone (p)ppGpp. However, persistence can occur stochastically in few cells even of stress-free bacterial populations. Growth of these cells could then be induced by the stress conditions. In this review, we focus on the persister formation of human intracellular bacterial pathogens, some of which belong to the most successful persister producers but lack some or even all of the assumed persistence-triggering factors and pathways. We propose a mechanism for the persister formation of these bacterial pathogens which is based on their specific intracellular bipartite metabolism. We postulate that this mode of metabolism ultimately leads, under certain starvation conditions, to the stalling of DNA replication initiation which may be causative for the persister state.

Keywords: ATP-DnaA complex; DNA replication initiation; intracellular bacterial pathogens; mechanisms of persister formation; persistence; stress conditions.

Figure 1

Bipartite metabolism of IBPs on the example of intracellular Listeria monocytogenes (Grubmüller et al., 2014; Eisenreich et al., 2017) showing various metabolic states and their possible significance for formation of persistence. (A) Host cell provides to intracellular L. monocytogenes a sufficient amount of glycerol as an energy source and a limited amount of glucose-6-phosphate used mainly for anabolic processes. (B) Host cell is unable to provide glucose-6-phosphate but can still provide a sufficient amount of glycerol which has now to be used by L. monocytogenes as energy source and for maintaining anabolic processes. (C) Host cell can only provide a limited amount of glycerol which is now mainly used by the intracellular bacteria as energy source to provide sufficient ATP for repair functions (mainly for DNA repair). Red arrows indicate mainly catabolic processes and green arrows anabolic processes. The thickness of the arrows indicates the strength of the processes under the given nutritional conditions. Dashed thin arrows indicate reactions that are no longer occurring or severely restricted under the given condition. Red-labelled ATP, NADH, and NADPH mean formation and blue ones consumption by the corresponding processes. See text, for further details.

Figure 2

Model showing the major processes necessary for the generation of the DNA initiation-active ATP-DnaA complex (green boxes and green arrows) and the factors, conditions and pathways (red boxes and red arrows) leading to inhibition of ATP-DnaA complex formation. Note that the latter situations are also identical to those leading to persister formation. OSR, oxidative stress response; GSR, general stress response; SSR, stringent stress response, leading to the generation of ppGpp via RelA and SpoT or Rsh. See text, for further details.