Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

Abstract

Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. Bacteria have evolved multiple strategies to cope with rapid and frequent changes in their environment. These survival strategies may include spore formation, increased production of polysaccharides, biofilm formation or escape from biofilms (i.e., switching from a motile into a sessile form and vice versa), altered motility, change of metabolic capabilities, response to antibiotics, and many more. In general, these switches are initiated by environmental or bacterially produced signals that are perceived by a diverse array of regulators and delegated into the corresponding regulatory networks. This presumably results in altered transcription levels of different genes or operons, which eventually causes a change in the phenotype and a response to the environmental stimulus. Within this context, it is generally assumed that the majority of a population will undergo this switch within a short time period and that the population will show a mostly homogeneous expression profile. During the last decade, it became, however, evident that a certain fraction of cells in an isogenic population behaves differently from the others, even though the environment may not have changed significantly. The term "phenotypic heterogeneity" thereby descr...

Quorum sensing signal–response systems in Gram-negative bacteria

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“…Placing such assets under collective control avoids exploitation of those goods. Nonetheless, recent evidence suggests that stochastic processes are also relevant; for example, phenotypic heterogeneity that stems from pathways that are controlled by quorum sensing may enable bet-hedging and division of labour among constituent members of a bacterial population 8 . How individual heterogeneity can be embedded in processes that are synchronously executed at the population level is being intensively investigated 9 .…”

Autonomous control of metabolic state by a quorum sensing (QS)-mediated regulator for bisabolene production in engineered E. coli

“…Many examples have used flow cytometric analyses to measure signal distribution of single gene response to QS systems (Grote et al, 2015). However, few has been reported that measures the population variation associated with QS-mediated metabolic pathway.…”

Heterogeneous regulation of bacterial natural product biosynthesis via a novel transcription factor

“…However, more and more examples arise showing that bacterial populations consist of genetically identical individual cells shaping different phenotypes, e.g. sporulation [1], bacterial competence [2], antibiotic production [3], or quorum sensing (see [4] for review). However, information about regulation mechanisms of bacterial phenotypic heterogeneity at the molecular level is rare to date.…”