The normalcy of dormancy: common themes in microbial quiescence

Abstract

All microorganisms are exposed to periodic stresses that inhibit growth. Many bacteria and fungi weather these periods by entering a hardy, nonreplicating state, often termed quiescence or dormancy. When this occurs during an infection, the resulting slowly growing pathogen is able to tolerate both immune insults and prolonged antibiotic exposure. While the stresses encountered in a free-living environment may differ from those imposed by host immunity, these growth-limiting conditions impose common pressures, and many of the corresponding microbial responses appear to be universal. In this review, we discuss the common features of these growth-limited states, which suggest new approaches for treating chronic infections such as tuberculosis.

Figure 1. Strategies to overcome growth-limiting stress

All microorganisms encounter periods during which growth is impossible. Three fundamental themes describe the strategies used to weather these periods. “Bust and boom” describes a strategy that relies on the dynamic persistence of a small subpopulation, “sporulation” is defined by the production of metabolically-inactive spores, and “quiescence” describes a metabolically-active non-replicating cell that is resistant to many environmental insults. These strategies differ in several important respects including the population density of persistent organisms, the sensitivity of these cells to toxins and antibiotics, and the differential dependence on rapid growth to repopulate the niche.

Figure 2. Common themes in microbial quiescence

Growth-arrest can be induced by many stimuli and can have a variety of consequences on the cell. Common growth limiting stresses encountered by environmental microbes and pathogens are shown. With a few notable exceptions, most of the growth-limiting stresses encountered in these environments are similar. Some responses to these insults are linked to a particular stress. For example, specific DNA repair pathways are necessary to resist oxidative and nitrosative stress, and the remodeling of carbon metabolism will be different in hypoxic versus normoxic conditions. In contrast, other responses appear to be secondary to growth arrest per se. For example, a wide variety of growth-inhibiting stresses trigger carbon storage and cell wall remodeling, and the maintenance of energy homeostasis is universally required for viability. PMF: proton motive force, ROS: reactive oxygen species, RNI: reactive nitrogen intermediate.