Persisters, persistent infections and the Yin-Yang model

Abstract

Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but can regrow under appropriate conditions. Persisters underlie persistent and latent infections and post-treatment relapse, posing significant challenges for the treatment of many bacterial infections. The current definition of persisters has drawbacks, and a Yin-Yang model is proposed to describe the heterogeneous nature of persisters that have to be defined in highly specific conditions. Despite their discovery more than 70 years ago, the mechanisms of persisters are poorly understood. Recent studies have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. These include toxin-antitoxin modules, stringent response, DNA repair or protection, phosphate metabolism, alternative energy production, efflux, anti-oxidative defense and macromolecule degradation. More sensitive single-cell techniques are required for a better understanding of persister mechanisms. Studies of bacterial persisters have parallels in other microbes (fungi, parasites, viruses) and cancer stem cells in terms of mechanisms and treatment approaches. New drugs and vaccines targeting persisters are critical for improved treatment of persistent infections and perhaps cancers. Novel treatment strategies for persisters and persistent infections are discussed.

Keywords: mechanisms; persistence; persisters; treatment strategies.

Figure 1

The Yin–Yang model of persisters and latent infections.^,, In a growing population of bacteria (Yang, red), there is a small population of non-growing or slowly growing persisters (Yin, black). In the persister population, there is a small number of growing bacteria (reverters). The persister population (Yin) or the growing population (Yang) is again heterogeneous and composed of various subpopulations with varying metabolic or dormant states in continuum in varying hierarchy (expressed by color from light to dark). The black spot in Yang (red) is connected to and the root of the Yin half (black), and the red spot in Yin, reverters, is connected to the Yang half (red). In the case of TB, INH kills growing bacteria (Yang) and RIF kills some growing bacteria, as well as slowly growing persisters, whereas PZA kills only persisters. Persisters not killed by antibiotics could revert to replicating forms (reverters) and cause relapse. The Yin–Yang model can be used to better describe latent infections (Yin) and active disease (Yang) at the host level and their respective interconversions.^, As drug treatment and immune responses inhibit or kill the growing bacteria (Yang) and some of the persisters, some persisters (Yin) still remain and the infection becomes latent (Yin), but may revert and cause relapse or sustained chronic infections with symptoms. In a hierarchical manner and among heterogeneous persister cell populations, there are a few true ‘stem' persister cells or mother cells (black spot in Yang) that have the capacity to derive other persisters (Yin) and initiate disease or cause reactivation. The Yin–Yang model proposes use of drugs targeting both replicating and non-replicating cells in combination or sequentially in a dynamic fashion and in cycles for better treatment of persistent bacterial infections. This Yin–Yang model can also be applied to other microbes, such as fungi, parasites, viruses, and their infections and even cancer and the respective treatments of infections and cancer.