Publications
107 results found
Mostowy RJ, Croucher NJ, De Maio N, et al., 2017, Frequent recombination of pneumococcal capsule highlights future risks of emergence of novel serotypes
<jats:title>Abstract</jats:title><jats:p>Capsular diversity of<jats:italic>Streptococcus pneumoniae</jats:italic>constitutes a major obstacle in eliminating the pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule polysaccharide locus (<jats:italic>cps</jats:italic>). However, the evolutionary dynamics of the capsule – the target of the currently used vaccines – remains not fully understood. Here, using genetic data from 4,469 bacterial isolates, we found<jats:italic>cps</jats:italic>to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of altered selection at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared to the rest of the genome. Analysis of twelve serogroups revealed their complex evolutionary history, which was principally driven by recombination with other serogroups and other streptococci. We observed significant variation in recombination rates between different serogroups. This variation could only be partially explained by the lineage-specific recombination rate, the remaining factors being likely driven by serogroup-specific ecology and epidemiology. Finally, we discovered two previously unobserved mosaic serotypes in the densely sampled collection from Mae La, Thailand, here termed 10X and 21X. Our results thus emphasise the strong adaptive potential of the bacterium by its ability to generate novel serotypes by recombination.</jats:p>
Lees JA, Vehkala M, Välimäki N, et al., 2016, Sequence element enrichment analysis to determine the genetic basis of bacterial phenotypes, Nature Communications, Vol: 7, ISSN: 2041-1723
Bacterial genomes vary extensively in terms of both gene content and gene sequence. This plasticity hampers the use of traditional SNP-based methods for identifying all genetic associations with phenotypic variation. Here we introduce a computationally scalable and widely applicable statistical method (SEER) for the identification of sequence elements that are significantly enriched in a phenotype of interest. SEER is applicable to tens of thousands of genomes by counting variable-length k-mers using a distributed string-mining algorithm. Robust options are provided for association analysis that also correct for the clonal population structure of bacteria. Using large collections of genomes of the major human pathogens Streptococcus pneumoniae and Streptococcus pyogenes, SEER identifies relevant previously characterized resistance determinants for several antibiotics and discovers potential novel factors related to the invasiveness of S. pyogenes. We thus demonstrate that our method can answer important biologically and medically relevant questions.
Croucher NJ, Mostowy R, Wymant C, et al., 2016, Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict, PLOS Biology, Vol: 14, ISSN: 1545-7885
Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs t
Marttinen P, Croucher NJ, Gutmann MU, et al., 2015, Recombination produces coherent bacterial species clusters in both core and accessory genomes., Microbial Genomics, Vol: 1, Pages: e000038-e000038, ISSN: 2057-5858
BACKGROUND: Population samples show bacterial genomes can be divided into a core of ubiquitous genes and accessory genes that are present in a fraction of isolates. The ecological significance of this variation in gene content remains unclear. However, microbiologists agree that a bacterial species should be 'genomically coherent', even though there is no consensus on how this should be determined. RESULTS: We use a parsimonious model combining diversification in both the core and accessory genome, including mutation, homologous recombination (HR) and horizontal gene transfer (HGT) introducing new loci, to produce a population of interacting clusters of strains with varying genome content. New loci introduced by HGT may then be transferred on by HR. The model fits well to a systematic population sample of 616 pneumococcal genomes, capturing the major features of the population structure with parameter values that agree well with empirical estimates. CONCLUSIONS: The model does not include explicit selection on individual genes, suggesting that crude comparisons of gene content may be a poor predictor of ecological function. We identify a clearly divergent subpopulation of pneumococci that are inconsistent with the model and may be considered genomically incoherent with the rest of the population. These strains have a distinct disease tropism and may be rationally defined as a separate species. We also find deviations from the model that may be explained by recent population bottlenecks or spatial structure.
Croucher NJ, Finkelstein JA, Pelton SI, et al., 2015, Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniae., Scientific Data, Vol: 2, ISSN: 2052-4463
Streptococcus pneumoniae is common nasopharyngeal commensal bacterium and important human pathogen. Vaccines against a subset of pneumococcal antigenic diversity have reduced rates of disease, without changing the frequency of asymptomatic carriage, through altering the bacterial population structure. These changes can be studied in detail through using genome sequencing to characterise systematically-sampled collections of carried S. pneumoniae. This dataset consists of 616 annotated draft genomes of isolates collected from children during routine visits to primary care physicians in Massachusetts between 2001, shortly after the seven valent polysaccharide conjugate vaccine was introduced, and 2007. Also made available are a core genome alignment and phylogeny describing the overall population structure, clusters of orthologous protein sequences, software for inferring serotype from Illumina reads, and whole genome alignments for the analysis of closely-related sets of pneumococci. These data can be used to study both bacterial evolution and the epidemiology of a pathogen population under selection from vaccine-induced immunity.
Li Y, Croucher NJ, Thompson CM, et al., 2015, Identification of pneumococcal colonization determinants in the stringent response pathway facilitated by genomic diversity, BMC Genomics, Vol: 16, ISSN: 1471-2164
BACKGROUND: Understanding genetic determinants of a microbial phenotype generally involves creating and comparing isogenic strains differing at the locus of interest, but the naturally existing genomic and phenotypic diversity of microbial populations has rarely been exploited. Here we report use of a diverse collection of 616 carriage isolates of Streptococcus pneumoniae and their genome sequences to help identify a novel determinant of pneumococcal colonization. RESULTS: A spontaneously arising laboratory variant (SpnYL101) of a capsule-switched TIGR4 strain (TIGR4:19F) showed reduced ability to establish mouse nasal colonization and lower resistance to non-opsonic neutrophil-mediated killing in vitro, a phenotype correlated with in vivo success. Whole genome sequencing revealed 5 single nucleotide polymorphisms (SNPs) affecting 4 genes in SpnYL101 relative to its ancestor. To evaluate the effect of variation in each gene, we performed an in silico screen of 616 previously published genome sequences to identify pairs of closely-related, serotype-matched isolates that differ at the gene of interest, and compared their resistance to neutrophil-killing. This method allowed rapid examination of multiple candidate genes and found phenotypic differences apparently associated with variation in SP_1645, a RelA/ SpoT homolog (RSH) involved in the stringent response. To establish causality, the alleles corresponding to SP_1645 were switched between the TIGR4:19F and SpnYL101. The wild-type SP_1645 conferred higher resistance to neutrophil-killing and competitiveness in mouse colonization. Using a similar strategy, variation in another RSH gene (TIGR4 locus tag SP_1097) was found to alter resistance to neutrophil-killing. CONCLUSIONS: These results indicate that analysis of naturally existing genomic diversity complements traditional genetics approaches to accelerate genotype-phenotype analysis.
Croucher NJ, Kagedan L, Thompson CM, et al., 2015, Selective and Genetic Constraints on Pneumococcal Serotype Switching, Plos Genetics, Vol: 11, ISSN: 1553-7404
Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishablepolysaccharide capsules (serotypes), which can be classified into “serogroups”based on cross-reactivity with certain antibodies. Pneumococci can alter their serotypethrough recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twentysuch “serotype switching” events were fully characterised using a collection of 616 wholegenome sequences from systematic surveys of pneumococcal carriage. Eleven of thesewere within-serogroup switches, representing a highly significant (p < 0.0001) enrichmentbased on the observed serotype distribution. Whereas the recombinations resulting in between-serogroupswitches all spanned the entire cps locus, some of those that caused within-serogroupswitches did not. However, higher rates of within-serogroup switching couldnot be fully explained by either more frequent, shorter recombinations, nor by genetic linkageto genes involved in β–lactam resistance. This suggested the observed pattern was aconsequence of selection for preserving serogroup. Phenotyping of strains constructed toexpress different serotypes in common genetic backgrounds was used to test whether genotypeswere physiologically adapted to particular serogroups. These data were consistentwith epistatic interactions between the cps locus and the rest of the genome that were specificto serotype, but not serogroup, meaning they were unlikely to account for the observeddistribution of capsule types. Exclusion of these genetic and physiological hypotheses suggestedfuture work should focus on alternative mechanisms, such as host immunity spanningmultiple serotypes within the same serogroup, which might explain the observedpattern.
Chang Q, Stevenson AE, Croucher NJ, et al., 2015, Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced, BMC INFECTIOUS DISEASES, Vol: 15
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- Citations: 22
Croucher NJ, Page AJ, Connor TR, et al., 2015, Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins, Nucleic Acids Research, Vol: 43, ISSN: 0305-1048
The emergence of new sequencing technologies has facilitated the use of bacterial whole genome alignments for evolutionary studies and outbreak analyses. These datasets, of increasing size, often include examples of multiple different mechanisms of horizontal sequence transfer resulting in substantial alterations to prokaryotic chromosomes. The impact of these processes demands rapid and flexible approaches able to account for recombination when reconstructing isolates’ recent diversification. Gubbins is an iterative algorithm that uses spatial scanning statistics to identify loci containing elevated densities of base substitutions suggestive of horizontal sequence transfer while concurrently constructing a maximum likelihood phylogeny based on the putative point mutations outside these regions of high sequence diversity. Simulations demonstrate the algorithm generates highly accurate reconstructions under realistically parameterized models of bacterial evolution, and achieves convergence in only a few hours on alignments of hundreds of bacterial genome sequences. Gubbins is appropriate for reconstructing the recent evolutionary history of a variety of haploid genotype alignments, as it makes no assumptions about the underlying mechanism of recombination. The software is freely available for download at github.com/sanger-pathogens/Gubbins, implemented in Python and C and supported on Linux and Mac OS X.
Croucher NJ, Didelot X, 2015, The application of genomics to tracing bacterial pathogen transmission, CURRENT OPINION IN MICROBIOLOGY, Vol: 23, Pages: 62-67, ISSN: 1369-5274
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- Citations: 61
Croucher NJ, Coupland PG, Stevenson AE, et al., 2014, Diversification of bacterial genome content through distinct mechanisms over different timescales, Nature Communications, Vol: 5, ISSN: 2041-1723
Bacterial populations often consist of multiple co-circulating lineages. Determining how such population structures arise requires understanding what drives bacterial diversification. Using 616 systematically sampled genomes, we show that Streptococcus pneumoniae lineages are typically characterized by combinations of infrequently transferred stable genomic islands: those moving primarily through transformation, along with integrative and conjugative elements and phage-related chromosomal islands. The only lineage containing extensive unique sequence corresponds to a set of atypical unencapsulated isolates that may represent a distinct species. However, prophage content is highly variable even within lineages, suggesting frequent horizontal transmission that would necessitate rapidly diversifying anti-phage mechanisms to prevent these viruses sweeping through populations. Correspondingly, two loci encoding Type I restriction-modification systems able to change their specificity over short timescales through intragenomic recombination are ubiquitous across the collection. Hence short-term pneumococcal variation is characterized by movement of phage and intragenomic rearrangements, with the slower transfer of stable loci distinguishing lineages.
Chewapreecha C, Marttinen P, Croucher NJ, et al., 2014, Comprehensive Identification of Single Nucleotide Polymorphisms Associated with Beta-lactam Resistance within Pneumococcal Mosaic Genes, PLOS GENETICS, Vol: 10, ISSN: 1553-7404
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- Citations: 128
Croucher NJ, Klugman KP, 2014, The Emergence of Bacterial "Hopeful Monsters", MBIO, Vol: 5, ISSN: 2150-7511
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- Citations: 22
Croucher NJ, Chewapreecha C, Hanage WP, et al., 2014, Evidence for Soft Selective Sweeps in the Evolution of Pneumococcal Multidrug Resistance and Vaccine Escape, GENOME BIOLOGY AND EVOLUTION, Vol: 6, Pages: 1589-1602, ISSN: 1759-6653
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- Citations: 74
Croucher NJ, Hanage WP, Harris SR, et al., 2014, Variable recombination dynamics during the emergence, transmission and 'disarming' of a multidrug-resistant pneumococcal clone, BMC BIOLOGY, Vol: 12, ISSN: 1741-7007
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- Citations: 58
Mostowy R, Croucher NJ, Hanage WP, et al., 2014, Heterogeneity in the frequency and characteristics of homologous recombination in pneumococcal evolution, PLoS Genetics, Vol: 10, ISSN: 1553-7390
The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro-recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes.
Lee GM, Kleinman K, Pelton SI, et al., 2014, Impact of 13-Valent Pneumococcal Conjugate Vaccination on Streptococcus pneumoniae Carriage in Young Children in Massachusetts., J Pediatric Infect Dis Soc, Vol: 3, Pages: 23-32
BACKGROUND: In April 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 for use in the United States. We evaluated rates of pneumococcal colonization, by serotype and antibiotic resistance, in Massachusetts communities where serial cross-sectional surveillance has been conducted for the past decade. METHODS: Nasopharyngeal swabs were obtained from children 0 to <7 years of age and seen by primary care providers for well child or acute illness visits in 2001, 2004, 2007, 2009, and 2011. Pneumococcal isolates were serotyped by Quellung reaction and classified as PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F), additional PCV13 serotypes (1, 3, 5, 6A, 7F, 19A), or non-PCV13 serotypes. Changes in colonization and impact of PCV13 were assessed using generalized linear mixed models, adjusting for known risk factors and accounting for clustering by community. RESULTS: Introduction of PCV13 did not affect the rate of overall pneumococcal colonization (31% in 2011). Colonization with non-PCV13 serotypes increased between 2001 and 2011 for all children (odds ratio [OR] per year, 1.12; 95% confidence interval [CI], 1.10, 1.15; P < .0001). 19A remained the second most common serotype in 2011, although a decline from 2009 was observed. Penicillin (7%), erythromycin (28%), ceftriaxone (10%), and clindamycin (10%) nonsusceptibility were commonly identified, concentrated among a small number of serotypes (including 19A, 35B, 15B/C, and 15A). Among healthy children 6-23 months old, colonization with PCV13 serotypes was lower among recipients of PCV13 vaccine (adjusted OR, 0.30; 95% CI, 0.11, 0.78). This effect was not observed in 6- to 23-month-old children with a concomitant respiratory tract infection (adjusted OR 1.36; 95% CI, 0.66, 2.77) or children 2 to <7 years old (adjusted OR, 1.17; 95% CI, 0.58, 2.34). CONCLUSIONS: 13-Valent pneumococcal conjugate vaccine reduced the prevalence of colonization with PCV13 serotypes among children 6-23 months old, b
Chewapreecha C, Harris SR, Croucher NJ, et al., 2014, Dense genomic sampling identifies highways of pneumococcal recombination, NATURE GENETICS, Vol: 46, Pages: 305-+, ISSN: 1061-4036
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- Citations: 260
Tasoulis S, Cheng L, Valimaki N, et al., 2014, Random Projection Based Clustering for Population Genomics, IEEE International Conference on Big Data, Publisher: IEEE, Pages: 675-682, ISSN: 2639-1589
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- Citations: 11
Wilf NM, Reid AJ, Ramsay JP, et al., 2013, RNA-seq reveals the RNA binding proteins, Hfq and RsmA, play various roles in virulence, antibiotic production and genomic flux in <i>Serratia</i> sp ATCC 39006, BMC GENOMICS, Vol: 14, ISSN: 1471-2164
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- Citations: 28
Croucher NJ, Mitchell AM, Gould KA, et al., 2013, Dominant Role of Nucleotide Substitution in the Diversification of Serotype 3 Pneumococci over Decades and during a Single Infection, PLOS GENETICS, Vol: 9, ISSN: 1553-7404
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- Citations: 53
Croucher NJ, Finkelstein JA, Pelton SI, et al., 2013, Population genomics of post-vaccine changes in pneumococcal epidemiology, NATURE GENETICS, Vol: 45, Pages: 656-+, ISSN: 1061-4036
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- Citations: 250
Croucher NJ, Harris SR, Grad YH, et al., 2013, Bacterial genomes in epidemiology-present and future, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 368, ISSN: 0962-8436
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- Citations: 37
Wyres KL, Lambertsen LM, Croucher NJ, et al., 2012, Pneumococcal Capsular Switching: A Historical Perspective, JOURNAL OF INFECTIOUS DISEASES, Vol: 207, Pages: 439-449, ISSN: 0022-1899
Background.Changes in serotype prevalence among pneumococcal populations result from both serotypereplacement and serotype (capsular) switching. Temporal changes in serotype distributions are well documented,but the contribution of capsular switching to such changes is unknown. Furthermore, it is unclear to what extentvaccine-induced selective pressures drive capsular switching.Methods.Serotype and multilocus sequence typing data for 426 pneumococci dated from 1937 through 2007 wereanalyzed. Whole-genome sequence data for a subset of isolates were used to investigate capsular switching events.Results.We identified 36 independent capsular switch events, 18 of which were explored in detail with whole-genome sequence data. Recombination fragment lengths were estimated for 11 events and ranged from approximately19.0 kb to≥58.2 kb. Two events took place no later than 1960, and the imported DNA included the capsular locusand the nearby penicillin-binding protein genespbp2xandpbp1a.Conclusions.Capsular switching has been a regular occurrence among pneumococcal populations throughout thepast 7 decades. Recombination of large DNA fragments (>30 kb), sometimes including the capsular locus and penicil-lin-binding protein genes, predated both vaccine introduction and widespread antibiotic use. This type of recombina-tion has likely been an intrinsic feature throughout the history of pneumococcal evolution.
Wyres KL, Lambertsen LM, Croucher NJ, et al., 2012, The multidrug-resistant PMEN1 pneumococcus is a paradigm for genetic success, Genome Biology, Vol: 13, ISSN: 1474-7596
Background:Streptococcus pneumoniae, also called the pneumococcus, is a major bacterial pathogen. Since its introduction in the 1940s, penicillin has been the primary treatment for pneumococcal diseases. Penicillin resistance rapidly increased among pneumococci over the past 30 years, and one particular multidrug-resistant clone, PMEN1, became highly prevalent globally. We studied a collection of 426 pneumococci isolated between 1937 and 2007 to better understand the evolution of penicillin resistance within this species.Results:We discovered that one of the earliest known penicillin-nonsusceptible pneumococci, recovered in 1967 from Australia, was the likely ancestor of PMEN1, since approximately 95% of coding sequences identified within its genome were highly similar to those of PMEN1. The regions of the PMEN1 genome that differed from the ancestor contained genes associated with antibiotic resistance, transmission and virulence. We also revealed that PMEN1 was uniquely promiscuous with its DNA, donating penicillin-resistance genes and sometimes many other genes associated with antibiotic resistance, virulence and cell adherence to many genotypically diverse pneumococci. In particular, we describe two strains in which up to 10% of the PMEN1 genome was acquired in multiple fragments, some as long as 32 kb, distributed around the recipient genomes. This type of directional genetic promiscuity from a single clone to numerous unrelated clones has, to our knowledge, never before been described.Conclusions:These findings suggest that PMEN1 is a paradigm of genetic success both through its epidemiology and promiscuity. These findings also challenge the existing views about horizontal gene transfer among pneumococci.
Li Y, Gierahn T, Thompson CM, et al., 2012, Distinct Effects on Diversifying Selection by Two Mechanisms of Immunity against <i>Streptococcus pneumoniae</i>, PLOS PATHOGENS, Vol: 8, ISSN: 1553-7366
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- Citations: 35
Everett DB, Cornick J, Denis B, et al., 2012, Genetic Characterisation of Malawian Pneumococci Prior to the Roll-Out of the PCV13 Vaccine Using a High-Throughput Whole Genome Sequencing Approach, PLOS ONE, Vol: 7, ISSN: 1932-6203
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- Citations: 34
Koeser CU, Holden MTG, Ellington MJ, et al., 2012, Rapid Whole-Genome Sequencing for Investigation of a Neonatal MRSA Outbreak, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 366, Pages: 2267-2275, ISSN: 0028-4793
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- Citations: 475
Croucher NJ, Harris SR, Barquist L, et al., 2012, A High-Resolution View of Genome-Wide Pneumococcal Transformation, PLOS PATHOGENS, Vol: 8, ISSN: 1553-7374
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- Citations: 74
Strouts FR, Power P, Croucher NJ, et al., 2012, Lineage-specific Virulence Determinants of Haemophilus influenzae Biogroup aegyptius, Emerging Infectious Diseases, Vol: 18, Pages: 449-457
An emergent clone of Haemophilus influenzae biogroup aegyptius (Hae) is responsible for outbreaks of Brazilian purpuric fever (BPF). First recorded in Brazil in 1984, the so-called BPF clone of Hae caused a fulminant disease that started with conjunctivitis but developed into septicemic shock; mortality rates were as high as 70%. To identify virulence determinants, we conducted a pan-genomic analysis. Sequencing of the genomes of the BPF clone strain F3031 and a noninvasive conjunctivitis strain, F3047, and comparison of these sequences with 5 other complete H. influenzae genomes showed that >77% of the F3031 genome is shared among all H. influenzae strains. Delineation of the Hae accessory genome enabled characterization of 163 predicted protein-coding genes; identified differences in established autotransporter adhesins; and revealed a suite of novel adhesins unique to Hae, including novel trimeric autotransporter adhesins and 4 new fimbrial operons. These novel adhesins might play a critical role in host-pathogen interactions.
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