Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments

Abstract

Phase-variation of genes is defined as the rapid and reversible switching of expression — either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of ‘sense-and-respond’ gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.

Enhancing bacterial survival through phenotypic heterogeneity

“…Phase variation is among the best characterized processes of generating phenotypic heterogeneity. Phase variation typically involves an ON and OFF switch in a phenotype that contributes to fitness in one environment but that may have a fitness cost in a different condition [3]. A number of genetic mechanisms that result in phase variation of a gene have been described, including slipped-strand mispairing in repetitive nucleotide tracts, DNA inversions by sitespecific recombinases, and allele shuffling by recombination (reviewed in [4]).…”

“…Phase variation typically regulates the production of complex structures, such as flagella, pili, fimbriae, and exopolysaccharides [3]. These structures are exposed on the bacterial surface and directly interface with the cell's environment.…”

Moraxella catarrhalis phase-variable loci show differences in expression during conditions relevant to disease

“…This variability is concentrated in surface-exposed regions, while their membrane-embedded regions are more conserved [68]. Antigenic variation is a feature of many outer-membrane proteins in various host adapted pathogens and aids in immune-evasion [49]. In addition, two further variants of UspA2 have been described: the hybrid UspA1-UspA2 protein known as UspA2H [16] and UspA2V [69].…”

“…In Haemophilus influenzae, at least nineteen predicted phase variable genes have been identified [38], including LOS synthesis [39][40][41], outer membrane proteins Hia [42] and HMW [43], as well the modA methyltransferase that is also found in Neisseria species [44][45][46][47]. Many of the studied phase variable genes are virulence factors and/or vaccine candidates [48,49]. Whilst phase variable candidates can be used in vaccines (for example, NadA in Bexsero [50][51][52]), there is the possibility of vaccine evasion due to phase variation.…”

Diversification of the restriction–modification system ofStreptococcus pyogenesthrough its acquisition of mobile elements

“…The roles of the RM system besides its function in the prokaryotic immune system have become more apparent in recent years. The type I specificity subunits of some bacterial species have been found to become switched with one another, thereby producing heterogeneity in gene expression (8)(9)(10)(11)(12). This "phase variation" can also contribute to control bacterial virulence, immune evasion, and niche adaptation (13).…”