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 lg… Show more
“…Such within-host μ resulted in the introduction of up to ≈41 substitutions more than would have been introduced via μ estimated over longer timescales in S. pneumoniae 13 and other bacterial species 38 . The within-episode N e ranged from 1.22 to 72.2 similar to those observed during short-term within-host Neisseria lactamica evolution 39 . Fig.…”
Section: Resultssupporting
confidence: 62%
“…Our results suggest that within-host evolution is adaptive since the occurrence of parallel mutations is unlikely to due to chance alone 39,51,52 . We showed that parallel SNPs are relatively more common than non-parallel SNPs in intergenic than genic regions, which could suggest that the non-coding regions are less constrained evolutionary than those in coding regions, which may be more deleterious, hence, more likely to be selected against.…”
Genomic evolution, transmission and pathogenesis of Streptococcus pneumoniae, an opportunistic human-adapted pathogen, is driven principally by nasopharyngeal carriage. However, little is known about genomic changes during natural colonisation. Here, we use wholegenome sequencing to investigate within-host microevolution of naturally carried pneumococci in ninety-eight infants intensively sampled sequentially from birth until twelve months in a high-carriage African setting. We show that neutral evolution and nucleotide substitution rates up to forty-fold faster than observed over longer timescales in S. pneumoniae and other bacteria drives high within-host pneumococcal genetic diversity. Highly divergent co-existing strain variants emerge during colonisation episodes through real-time intra-host homologous recombination while the rest are co-transmitted or acquired independently during multiple colonisation episodes. Genic and intergenic parallel evolution occur particularly in antibiotic resistance, immune evasion and epithelial adhesion genes. Our findings suggest that withinhost microevolution is rapid and adaptive during natural colonisation.
“…Such within-host μ resulted in the introduction of up to ≈41 substitutions more than would have been introduced via μ estimated over longer timescales in S. pneumoniae 13 and other bacterial species 38 . The within-episode N e ranged from 1.22 to 72.2 similar to those observed during short-term within-host Neisseria lactamica evolution 39 . Fig.…”
Section: Resultssupporting
confidence: 62%
“…Our results suggest that within-host evolution is adaptive since the occurrence of parallel mutations is unlikely to due to chance alone 39,51,52 . We showed that parallel SNPs are relatively more common than non-parallel SNPs in intergenic than genic regions, which could suggest that the non-coding regions are less constrained evolutionary than those in coding regions, which may be more deleterious, hence, more likely to be selected against.…”
Genomic evolution, transmission and pathogenesis of Streptococcus pneumoniae, an opportunistic human-adapted pathogen, is driven principally by nasopharyngeal carriage. However, little is known about genomic changes during natural colonisation. Here, we use wholegenome sequencing to investigate within-host microevolution of naturally carried pneumococci in ninety-eight infants intensively sampled sequentially from birth until twelve months in a high-carriage African setting. We show that neutral evolution and nucleotide substitution rates up to forty-fold faster than observed over longer timescales in S. pneumoniae and other bacteria drives high within-host pneumococcal genetic diversity. Highly divergent co-existing strain variants emerge during colonisation episodes through real-time intra-host homologous recombination while the rest are co-transmitted or acquired independently during multiple colonisation episodes. Genic and intergenic parallel evolution occur particularly in antibiotic resistance, immune evasion and epithelial adhesion genes. Our findings suggest that withinhost microevolution is rapid and adaptive during natural colonisation.
“…Excluding SSR, our WGS analysis indicated an average of 1.02 mutations/genome/month of carriage (i.e., 6.1 ϫ 10 Ϫ6 mutations/site/year). Comparable rates were obtained by Lamelas et al (35) for serogroup A meningococci (3.1 ϫ 10 Ϫ6 substitutions/site/year), from analysis of 100 isolates representing an 8-year study in a single Ghanaian district, and Pandey et al (33) for Neisseria lactamica (2.2 ϫ 10 Ϫ6 ; 27 volunteers) and N. meningitidis (9.3 ϫ 10 Ϫ7 ; 7 volunteers), using longitudinal isolates from a volunteer study. Meningococcal mutation rates for rifampin resistance are 2.6 ϫ 10 Ϫ9 mutations/division (36), equivalent to 2.2 ϫ 10 Ϫ5 mutations/site/year.…”
Section: Figmentioning
confidence: 66%
“…However, this variation arises from processes occurring in individual carriers, which is poorly characterized. Recent studies by Pandey et al (33) and Borud et al (34) detected evidence of transient and fixed genetic variants during persistent neisserial carriage but were limited by having only one isolate per time point. Using samples from a 2008 -2009 meningococcal carriage study wherein nasopharyngeal swabs were deliberately plated to yield multiple single colonies (see Alamro et al [23]), we performed both WGS and allele-specific PCR on 6 to 10 isolates/time point from multiple sequential time points from several volunteers.…”
Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Neisseria meningitidis. Interrogation of whole-genome sequences for paired isolates from 25 carriers showed that de novo mutations were infrequent, while horizontal gene transfer occurred in 16% of carriers. Examination of multiple isolates per time point enabled separation of sporadic and transient allelic variation from directional variation. A comprehensive comparative analysis of directional allelic variation with hypermutation of simple sequence repeats and hyperrecombination of class 1 type IV pilus genes detected an average of seven events per carrier and 2:1 bias for changes due to localized hypermutation. Directional genetic variation was focused on the outer membrane with 69% of events occurring in genes encoding enzymatic modifiers of surface structures or outer membrane proteins. Multiple carriers exhibited directional and opposed switching of allelic variants of the surface-located Opa proteins that enables continuous expression of these adhesins alongside antigenic variation. A trend for switching from PilC1 to PilC2 expression was detected, indicating selection for specific alterations in the activities of the type IV pilus, whereas phase variation of restriction modification (RM) systems, as well as associated phasevarions, was infrequent. We conclude that asymptomatic meningococcal carriage on mucosal surfaces is facilitated by frequent localized hypermutation and horizontal gene transfer affecting genes encoding surface modifiers such that optimization of adhesive functions occurs alongside escape of immune responses by antigenic variation.
IMPORTANCE Many bacterial pathogens coexist with host organisms, rarely causing disease while adapting to host responses. Neisseria meningitidis, a major cause of meningitis and septicemia, is a frequent persistent colonizer of asymptomatic teenagers/young adults. To assess how genetic variation contributes to host persistence, whole-genome sequencing and hypermutable sequence analyses were performed on multiple isolates obtained from students naturally colonized with meningococci. High frequencies of gene transfer were observed, occurring in 16% of carriers and affecting 51% of all nonhypermutable variable genes. Comparative analyses showed that hypermutable sequences were the major mechanism of variation, causing 2-fold more changes in gene function than other mechanisms. Genetic variation was focused on genes affecting the outer membrane, with directional changes in proteins responsible for bacterial adhesion to host surfaces. This comprehensive examination of genetic plasticity in individual hosts provides a significant new platform for rationale design of approaches to prevent the spread of this pathogen.
“…In serogroup A carriage isolates from Africa, the mutation rate was 6.2 nucleotide substitutions per year [34]. And in a small cohort of meningococcal carriage isolates, the mutation rate was 1.9 nucleotide substitutions per year [35]. Unpublished results from a large cohort of over 2500 carriage isolates from West Africa, showed the median mutation rate to be 5.94 (range 1.12–11.3).…”
We studied population genomics of 486
Neisseria meningitidis
isolates causing meningitis in the Netherlands during the period 1979–2003 and 2006–2013 using whole-genome sequencing to evaluate the impact of a hyperendemic period of serogroup B invasive disease. The majority of serogroup B isolates belonged to ST-41/44 (41 %) and ST-32 complex (16 %). Comparing the time periods, before and after the decline of serogroup B invasive disease, there was a decrease of ST-41/44 complex sequences (P=0.002). We observed the expansion of a sub-lineage within ST-41/44 complex sequences being associated with isolation from the 1979–2003 time period (P=0.014). Isolates belonging to this sub-lineage expansion within ST-41/44 complex were marked by four antigen allele variants. Presence of these allele variants was associated with isolation from the 1979–2003 time period after correction for multiple testing (Wald test, P=0.0043 for FetA 1–5; P=0.0035 for FHbp 14; P=0.012 for PorA 7–2.4 and P=0.0031 for NHBA two peptide allele). These sequences were associated with 4CMenB vaccine coverage (Fisher’s exact test, P<0.001). Outside of the sub-lineage expansion, isolates with markedly lower levels of predicted vaccine coverage clustered in phylogenetic groups showing a trend towards isolation in the 2006–2013 time period (P=0.08). In conclusion, we show the emergence and decline of a sub-lineage expansion within ST-41/44 complex isolates concurrent with a hyperendemic period in meningococcal meningitis. The expansion was marked by specific antigen peptide allele combinations. We observed preliminary evidence for decreasing 4CMenB vaccine coverage in the post-hyperendemic period.
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