Abstract
Pathogens continuously adapt to changing host environments where variation in their virulence and antigenicity is critical to their long-term evolutionary success. The emergence of novel variants is accelerated in microbial mutator strains (mutators) deficient in DNA repair genes, most often from mismatch repair and oxidized-guanine repair systems (MMR and OG respectively). Bacterial MMR/OG mutants are abundant in clinical samples and show increased adaptive potential in experimental infection models, yet the role of mutators in the epidemiology and evolution of infectious disease is not well understood. Here we investigated the role of mutation rate dynamics in the evolution of a broad host range pathogen, Streptococcus iniae, using a set of 80 strains isolated globally over 40 years. We have resolved phylogenetic relationships using non-recombinant core genome variants, measured in vivo mutation rates by fluctuation analysis, identified variation in major MMR/OG genes and their regulatory regions, and phenotyped the major traits determining virulence in streptococci. We found that both mutation rate and MMR/OG genotype are remarkably conserved within phylogenetic clades but significantly differ between major phylogenetic lineages. Further, variation in MMR/OG loci correlates with occurrence of atypical virulence-associated phenotypes, infection in atypical hosts (mammals), and atypical (osseous) tissue of a vaccinated primary host. These findings suggest that mutators are likely to facilitate adaptations preceding major diversification events and may promote emergence of variation permitting colonization of a novel host tissue, novel host taxa (host jumps), and immune-escape in the vaccinated host.
Highlights
Mutation rates in microbial populations are a trade-off between maintenance of genetic integrity and evolvability [1, 2]
Bacteria can efficiently fluctuate between high and low mutation regimes: While extremely low mutation rates are maintained in favourable conditions [5], elevation of mutation rates known as stress-induced mutagenesis (SIM) occurs in adapting populations [6, 7]
We investigate the role of mutators and mutation rate dynamics in the epidemiology and evolution of Streptococcus iniae S. iniae the broad host-range pathogen is a highly adaptable species, evidenced by its global distribution, ability to cross divergent host taxa boundaries and repeated re-infection of previously immunised hosts during disease outbreaks [64, 65]
Summary
Heritable hypermutable strains deficient in DNA repair genes (mutators) facilitate microbial adaptation as they may rapidly generate beneficial mutations. S. iniae mutation rate phenotype and genotype are strongly associated with phylogenetic diversification and variation in major streptococcal virulence determinants (capsular polysaccharide, hemolysin, cell chain length, resistance to oxidation, and biofilm formation). Profound changes in virulence determinants observed in mammalian isolates (atypical host) and vaccine-escape isolates found in bone (atypical tissue) of vaccinated barramundi are linked to multiple MMR and OG variants and unique mutation rates. This implies that adaptation to new host taxa, new host tissue, and to immunity of a vaccinated host is promoted by mutator strains. Our findings support the importance of mutation rate dynamics in evolution of pathogenic bacteria, in particular adaptation to a drastically different immunological setting that occurs during host jump and vaccine escape events
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