Abstract
Rapid adaptation to fluctuations in the host milieu contributes to the host persistence and virulence of bacterial pathogens. Adaptation is frequently mediated by hypermutable sequences in bacterial pathogens. Early bacterial genomic studies identified the multiplicity and virulence-associated functions of these hypermutable sequences. Thus, simple sequence repeat tracts (SSRs) and site-specific recombination were found to control capsular type, lipopolysaccharide structure, pilin diversity and the expression of outer membrane proteins. We review how the population diversity inherent in the SSR-mediated mechanism of localised hypermutation is being unlocked by the investigation of whole genome sequences of disease isolates, analysis of clinical samples and use of model systems. A contrast is presented between the problematical nature of analysing simple sequence repeats in next generation sequencing data and in simpler, pragmatic PCR-based approaches. Specific examples are presented of the potential relevance of this localized hypermutation to meningococcal pathogenesis. This leads us to speculate on the future prospects for unravelling how hypermutable mechanisms may contribute to the transmission, spread and persistence of bacterial pathogens.
Highlights
Adaptability is a common feature of bacterial pathogens
This study investigated the changes in the phase variable genes of C. jejuni during the colonization of four-week old chickens
The first stage of pathogenomics has placed the emphasis on comparisons between bacterial isolates from outbreaks and epidemics, disease versus carriage, different isolation sites within a host and alternate types of disease presentation
Summary
Adaptability is a common feature of bacterial pathogens. The rapidly changing milieu of an inflammatory host environment and traversing between host tissues with their differing nutrient contents and innate/adaptive immune effectors requires the induction of a diverse set of defence/attack molecules and metabolic pathways by the bacterial cells. Stochastic generation of phenotypic variation by “hypermutable” mechanisms is a widespread adaptive phenomenon that has evolved within the genomes of several bacterial pathogens as a response to these forces [1,2,3,4]. The prevalence of these mechanisms in disease isolates and the amounts of variation manifest during disease is amenable to high throughput global analysis. Evolution has acted on these sequences, sometimes in combination with trans-acting factors, to evolve loci with mutation rates up to 1 × 10−3 per division [7] This heightened mutability is referred to as localised hypermutation and is contained in ‘contingency’. This review will consider only SSR-mediated hypermutation and highlight some examples of how research into these types of contingency loci is improving our understanding of aspects of bacterial pathogenesis
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