Diversity-Generating Machines: Genetics of Bacterial Sugar-Coating

Abstract

Bacterial pathogens and commensals are surrounded by diverse surface polysaccharides which include capsules and lipopolysaccharides. These carbohydrates play a vital role in bacterial ecology and interactions with the environment. Here, we review recent rapid advancements in this field, which have improved our understanding of the roles, structures, and genetics of bacterial polysaccharide antigens. Genetic loci encoding the biosynthesis of these antigens may have evolved as bacterial diversity-generating machines, driven by selection from a variety of forces, including host immunity, bacteriophages, and cell-cell interactions. We argue that the high adaptive potential of polysaccharide antigens should be taken into account in the design of polysaccharide-targeting medical interventions like conjugate vaccines and phage-based therapies.

Keywords: ecology; glycans; phage therapy; polysaccharide; recombination; vaccine.

Figure 1

Generation of Polysaccharide Diversity in Bacteria. Polysaccharide antigens, like capsules and O-antigens, are usually synthesised by a specialist group of enzymes which are encoded by genes located in an antigen-biosynthesis locus. The genetic architecture of these loci is often similar between different, even distantly related, bacterial species. The specialised polymer-specific genes (coloured cassettes), which encode transferase enzymes (coloured shapes), are typically located in the middle of the locus. They are flanked by conserved, regulatory or transport genes (grey cassettes). The polymer-specific genes synthesise a monomer (so-called repeat unit), which is then polymerised to a polysaccharide chain and transported outside the cell. The order of these two events depends on the synthesis pathway, which, in the majority of studied cases, belongs to either the wzy-dependent or the ABC-dependent class. A given combination of the polymer-specific genes is a strong predictor of the polysaccharide structure, and thus bacterial serological type (serotype).

Figure 2

Factors Driving and Maintaining Diversity of Polysaccharide Antigens. (A) Major diversifying forces in the world of bacterial polysaccharide antigens: host immunity, bacteriophages, and cell–cell interactions (including host glycan diversity, eukaryotic predators and other host commensals). These forces are likely to drive and maintain the polysaccharide antigen diversity we observe today. (B) These factors should not be viewed as mutually exclusive, but rather as different forces operating at different scales of time and space. Coevolution with bacteriophages could select for novel polysaccharide diversity on short timescales from just a few bacterial generations, could occur within virtually any ecological niche including host associated or non-host associated, and could have transient or long-lasting impacts on both bacterial and phage population dynamics. The impact of genetic variation in host glycan diversity is expected to take much longer to affect bacterial population structures, depending on host diversity and generation times. Host immunity, the diversity of other host commensals, and the impact of predators are likely to operate somewhere between the two. Phages may promote within-host diversity of antigens, but a serotype which provides resistance against a given phage population may not spread in the population due to its low between-host fitness. Likewise, glycan diversity in different host populations may promote diversity over space: different populations found in different locations may promote different bacterial antigens, but a single type within each population.

Figure I

Mechanisms of Bacterial Adaptation against Polysaccharide Conjugate Vaccines. (A) Impact of polysaccharide conjugate vaccines on bacterial population structure. On the left, introduction of the vaccine against the red serotype is followed by the decline of this serotype but no replacement by another strain with the blue serotype, and thus overall reduction in carriage rates. This is similar to the situation in Haemophilus influenzae . In the middle, vaccination against the red serotype is followed by the rise of another lineage (triangle) with the blue serotype with no significant reduction in carriage, known as ‘serotype replacement’. On the right, vaccination against the red serotype is followed the rise of the same lineage (square) with another serotype (blue). This is a result of an acquisition of the blue serotype by the square lineage (known as ‘serotype switching’), which had occurred prior to the introduction of the vaccine. The latter two situations are frequently observed in Streptococcus pneumoniae. (B) Potential impact of antigenic diversification on multivalent vaccine strategies. On the left, it is assumed that serotypes do not diversify over time. In this theoretical scenario, broader, multivalent vaccines could eventually lead to the eradication of the bacterial disease. On the right, new serotypes constantly emerge at low frequencies and are selected for by the vaccine due to serotype replacement. This scenario represents a Red Queen race between the vaccines and bacteria. In such a case, broader vaccines could select for novel, previously unseen serotypes to rise in frequency.