Individuality, phenotypic differentiation, dormancy and ‘persistence’ in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology

Abstract

For bacteria, replication mainly involves growth by binary fission. However, in a very great many natural environments there are examples of phenotypically dormant, non-growing cells that do not replicate immediately and that are phenotypically 'nonculturable' on media that normally admit their growth. They thereby evade detection by conventional culture-based methods. Such dormant cells may also be observed in laboratory cultures and in clinical microbiology. They are usually more tolerant to stresses such as antibiotics, and in clinical microbiology they are typically referred to as 'persisters'. Bacterial cultures necessarily share a great deal of relatedness, and inclusive fitness theory implies that there are conceptual evolutionary advantages in trading a variation in growth rate against its mean, equivalent to hedging one's bets. There is much evidence that bacteria exploit this strategy widely. We here bring together data that show the commonality of these phenomena across environmental, laboratory and clinical microbiology. Considerable evidence, using methods similar to those common in environmental microbiology, now suggests that many supposedly non-communicable, chronic and inflammatory diseases are exacerbated (if not indeed largely caused) by the presence of dormant or persistent bacteria (the ability of whose components to cause inflammation is well known). This dormancy (and resuscitation therefrom) often reflects the extent of the availability of free iron. Together, these phenomena can provide a ready explanation for the continuing inflammation common to such chronic diseases and its correlation with iron dysregulation. This implies that measures designed to assess and to inhibit or remove such organisms (or their access to iron) might be of much therapeutic benefit.

A Dormant Microbial Component in the Development of Preeclampsia

“…This is also very well established [e.g., Ref. (139, 190–203)]. In many cases, they can hide intracellularly (204), where antibiotics often penetrate poorly (205) because the necessary transporters (206–209) are absent.…”

“…Indeed, we have shown that absolutely tiny (highly substoichiometric) amounts of LPS can have a massive effect on the blood clotting process (257), potentially inducing β-amyloid formation directly (258, 259) [something, interestingly, that can be mimicked in liquid crystals (260, 261)]. The overall series of interactions envisaged [see also Kell et al (139)] is shown in Figure 6.…”

“…This has led to the recognition (128, 139, 141) that the source of the continuing inflammation might be iron-based resuscitation of dormant microbes that could release well known and highly potent inflammagens such as LPS. Indeed, we have shown that absolutely tiny (highly substoichiometric) amounts of LPS can have a massive effect on the blood clotting process (257), potentially inducing β-amyloid formation directly (258, 259) [something, interestingly, that can be mimicked in liquid crystals (260, 261)].…”

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…While microbes even of the same genotype are purposely highly heterogeneous physiologically [311,312], even in the same media, the biotechnologist might wish to turn on and off pathways in 'all' cells at once; 'quorum sensing' methods are one means to seek to do this [169,313].…”

The metabolome 18 years on: a concept comes of age

“…(However, we note as a caveat that most microbes have still not been brought into laboratory culture and their many secondary metabolites decrypted (Kell et al 2015a; Lewis et al 2010)).…”