Abstract
Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutually-excluding relationship with the pathogen Neisseria meningitidis. Here we report controlled human infection with genomically-defined N. lactamica and subsequent bacterial microevolution during 26 weeks of colonisation. We find that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions (pgl and lgt) and iron acquisition (fetA promotor and hpuA). Recurrent polymorphisms occurred in genes associated with energy metabolism (nuoN, rssA) and the CRISPR-associated cas1. A gene encoding a large hypothetical protein was often mutated in 27% of the subjects. In volunteers who were naturally co-colonised with meningococci, recombination altered allelic identity in N. lactamica to resemble meningococcal alleles, including loci associated with metabolism, outer membrane proteins and immune response activators. Our results suggest that phase variable genes are often mutated during carriage-associated microevolution.
Highlights
Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutuallyexcluding relationship with the pathogen Neisseria meningitidis
Genetic diversity can be caused by phase variation resulting from random slipped-strand mispairing in hypermutable, repetitive, polymeric sequences in ‘contingency loci’, such as the lipooligosaccharide biosynthetic genes[5,6,7]
Regarding the nasopharyngeal pathogen Neisseria meningitidis, a study contrasting bloodstream and nasal isolates from four individuals found no evidence of gene-specific convergent evolution but detected phase variation in type IV pilus biogenesis loci[12]
Summary
Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutuallyexcluding relationship with the pathogen Neisseria meningitidis. Genetic diversity can be caused by phase variation resulting from random slipped-strand mispairing in hypermutable, repetitive, polymeric sequences in ‘contingency loci’, such as the lipooligosaccharide biosynthetic genes[5,6,7]. These can drive host- or population-specific, selection bottlenecks[8]. Regarding the nasopharyngeal pathogen Neisseria meningitidis, a study contrasting bloodstream and nasal isolates from four individuals found no evidence of gene-specific convergent evolution but detected phase variation in type IV pilus biogenesis loci[12]. We used two controlled human infection studies to examine the microevolution of N. lactamica, a harmless commensal, genetically and phenotypically similar to N. meningitidis and Neisseria gonnorhoeae[14]. A second study, the purpose of which was to explore the potential, protective effect of N. lactamica colonisation in young adults, a demographic at risk of Neisseria infection[15], examined inoculated N. lactamica, other wild-type N. lactamica and wild-type N. meningitidis collected[16], over 6 months of carriage
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