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Proc Natl Acad Sci U S A. Mar 4, 2008; 105(9): 3473–3478.
Published online Feb 27, 2008. doi:  10.1073/pnas.0800151105
PMCID: PMC2265139

Whole-genome comparison of disease and carriage strains provides insights into virulence evolution in Neisseria meningitidis


Neisseria meningitidis is a leading cause of infectious childhood mortality worldwide. Most research efforts have hitherto focused on disease isolates belonging to only a few hypervirulent clonal lineages. However, up to 10% of the healthy human population is temporarily colonized by genetically diverse strains mostly with little or no pathogenic potential. Currently, little is known about the biology of carriage strains and their evolutionary relationship with disease isolates. The expression of a polysaccharide capsule is the only trait that has been convincingly linked to the pathogenic potential of N. meningitidis. To gain insight into the evolution of virulence traits in this species, whole-genome sequences of three meningococcal carriage isolates were obtained. Gene content comparisons with the available genome sequences from three disease isolates indicate that there is no core pathogenome in N. meningitidis. A comparison of the chromosome structure suggests that a filamentous prophage has mediated large chromosomal rearrangements and the translocation of some candidate virulence genes. Interspecific comparison of the available Neisseria genome sequences and dot blot hybridizations further indicate that the insertion sequence IS1655 is restricted only to N. meningitidis; its low sequence diversity is an indicator of an evolutionarily recent population bottleneck. A genome-based phylogenetic reconstruction provides evidence that N. meningitidis has emerged as an unencapsulated human commensal from a common ancestor with Neisseria gonorrhoeae and Neisseria lactamica and consecutively acquired the genes responsible for capsule synthesis via horizontal gene transfer.

Keywords: comparative genomics, genome evolution, bacterial capsule, neisserial prophage, IS1655

The meningococcus Neisseria meningitidis is a bacterial commensal of the human nasopharynx and for reasons that are still mostly unknown occasionally causes septicemia and meningitis (1). Because of the high lethality and frequent long-term sequelae in survivors, most of the experimental work on pathogenesis has focused on disease strains so far. However, multilocus sequence typing (MLST) (2) has revealed that most cases of disease are caused by only very few clonal complexes of related sequence types (STs) referred to as hypervirulent lineages (2) and that isolates belonging to these hypervirulent lineages are underrepresented in healthy carriers (35). In turn, >10% of the healthy population are colonized with N. meningitidis and most carriage isolates were found to belong to a bewildering variety of >2,000 different sequence types that rarely, if ever, cause disease.

The genetic basis for the observed virulence differences is still a matter of investigation (6). Because of the lack of an appropriate animal model, most insight in pathogenicity factors of N. meningitidis resulted from in vitro studies with cell cultures, and thus the in vivo relevance for most of these candidate virulence factors still remains to be validated (7). One of the well established virulence factors in N. meningitidis is the polysaccharide capsule (8), which mediates resistance against complement-mediated lysis and opsonophagocytosis (9). Based on the chemical composition and the immunological characteristics of their capsular polysaccharide, meningococci are divided into 13 serogroups with serogroups A–C, W-135, and Y being most frequently associated with human disease (10). However, although carriage isolates are frequently constitutively unencapsulated because of a lack of the genetic island encoding capsule synthesis (11), several carriage isolates express polysaccharide capsules otherwise associated with disease (35). These observations suggest that the capsule is necessary, but not sufficient to confer virulence.

For N. meningitidis, the genomes of three disease isolates belonging to different hypervirulent lineages have been annotated and published (1214). Based on these three genomes, comparative genomic hybridization (CGH) studies highlighted the presence of a filamentous prophage termed Nf1 (15) in the genomes of several, but not all hypervirulent lineages (16, 17). Again, its contribution to virulence in these isolates is currently unresolved because it does not code for any known virulence factor.

Here, we provide the genome sequences of three meningococcal carriage strains including the complete genome of an constitutively unencapsulated meningococcal strain belonging to a clonal complex that is frequently recovered from healthy carriers (3). Whole-genome comparisons of the disease and carriage genomes were performed to analyze possible mechanisms of chromosome structure variation, to search for genes that are specific for disease isolates and to gain insight into the evolutionary relationships between the sequenced disease and carriage strains.

Results and Discussion

General Features of the Meningococcal Genomes.

All three meningococcal strains sequenced in this study belong to different multilocus sequence types and were isolated from healthy carriers during a carriage study performed in 1999/2000 in Bavaria, Germany (3). Strains α153 and α275 belong to the serogroups 29E and W-135, respectively, whereas strain α14 contains the so-called capsule null locus (cnl) and thus is incapable of capsule production (11) (Table 1).

Table 1.
Comparative overview of the sequenced meningococcal genomes

The three newly sequenced genomes and the genomes of N. meningitidis serogroup A strain Z2491 (13), serogroup B strain MC58 (14), and serogroup C strain FAM18 (12) already available in the databases were used for subsequent analysis (Table 1). In the following, the six strains will be referred to as α14, α153, α275, Z2491, MC58, and FAM18, respectively. All genomes revealed similar benchmark data such as genome size, GC content, or number of predicted genes (Table 1). The extrapolated number of genes belonging to the meningococcal core genome is at least 1,337 [CI0.95 = (1312.8; 1361.2)] and the number of new genes contributed by each new N. meningitidis genome is predicted to be at least 43 [CI0.95 = (38.3; 48.7)]. This indicates that the pangenome of N. meningitidis is open (18) and that new genes continue to be added to the gene pool of N. meningitidis any time a new strain is sequenced. Therefore, the construction of a “pan-Neisseria” microarray (19, 20) capturing the entire meningococcal gene pool might be an elusive goal.

The Meningococcal Pathogenome.

Whole-genome comparisons further showed that there is no consistent difference in the distribution of most of the hitherto-studied candidate virulence genes between carriage and disease isolates. In fact, of the 134 genes listed in a recent compilation of candidate virulence genes found in N. meningitidis (19, 21), 115 can also be found in the carriage isolates [supporting information (SI) Table 2]. Of the remaining 19 genes found exclusively in the disease isolates, only NMA2123 coding for an FrpC-related RTX-family exoprotein in Z2491 was also found to be present in all sequenced disease isolates. However, a number of paralogous proteins to NMA2123 are encoded also in the genomes of the three carriage isolates. Surprisingly, when compared with all of the genes contained in the meningococcal pangenome, a higher proportion of these candidate virulence genes belong to the meningococcal core genome and only very few are restricted to only one strain (Fig. 1).

Fig. 1.
Analysis of the meningococcal pathogenome. (A) Distribution of different classes of genes among the different genomic compartments. Depicted is the partition of all genes from the species pangenome (gray bar), genes having a low GC content and probably ...

In a complementary approach, the number of genes that are shared by all disease isolates but are absent from all carriage isolates was calculated for different combinations of disease and carriage isolates. The size of this so-defined core pathogenome declines sharply with increasing number of genomes compared and comprises ≈11 genes when all six strains are included (Fig. 1). According to the annotation of Z2491, the genes NMA1792–NMA1799 belong to the filamentous prophage Nf1 (15), which was recently shown to be specific only for certain hypervirulent lineages but absent in others (16, 17). The remaining three genes are all located on the fha locus in Z2491. NMA0692 putatively encodes an alternative C-terminal cassette for the effector protein (HrpA) of the meningococcal two-partner secretion system (TPS). However, paralogous genes encoding a complete TPS are present in all carriage isolates analyzed and are likely to be present in all meningococcal clonal lineages (22). Finally, NMA0693 has some sequence similarity to a predicted soluble lytic transglycosylase from Vibrio vulnificus (GenBank NP_762383), and NMA0694 encodes a hypothetical protein. Although NMA0692 and NMA0694 were both shown to be expressed in N. meningitidis on contact with human epithelial cells in vitro (23), it remains questionable whether these genomic differences might also translate into virulence differences.

In line with previous CGH studies (16, 17, 19, 20), our data suggest that, in N. meningitidis, most of the so-far-studied candidate virulence genes should more appropriately be considered as fitness genes being involved in, e.g., colonization of the human nasopharynx and not as virulence factors for the invasion of host tissues.

Mechanisms of Chromosome Structure Variation in N. meningitidis.

With respect to the chromosome of α14, the chromosomes of the three disease strains harbor large symmetrical inversions around the origin of replication (oriC) and a number of smaller translocations/inversions (Fig. 2). Of the five inversions shown in Fig. 2, two are flanked by insertion sequence (IS) elements and another two by so-called dRS3 repeats. The large inversion around oriC seen in the MC58 was already shown to be associated with the integration of a circular extrachromosomal element (24).

Fig. 2.
Annotated multiple whole-genome alignment. For each genome, the order of LCBs is given as a series of colored blocks with the putative origin of replication designated oriC being indicated by a black rectangle. The genomic locations of dRS3 elements are ...

The 568-kb region inverted around oriC in FAM18 is flanked by (truncated) IS1101 elements (IS5 family). By forming composite transposons, ISNme1 (IS5 family) elements probably mediated the translocation of a 10-kb region in FAM18 (designated T1 in Fig. 2) containing genes for a hemolysin and an ABC transporter, and the translocation of lbpAB encoding a surface receptor for human lactoferrin in the three disease isolates.

dRS3 elements are a family of 20-bp repeats with conserved 6-bp terminal inverted repeats. They occur almost 700 times in the meningococcal genome (Fig. 2 and Table 1). In Z2491, the 75-kb region inverted around oriC (designated Inv1 in Fig. 2) is flanked on either sides by dRS3 repeat arrays and a 20-kb region that is inverted in the three disease isolates with respect to α14 (designated Inv2 in Fig. 2). Recombination at dRS3 elements might also have led to the deletion of pilC1 in α14 and of hpuAB in FAM18 and Z2491, respectively, and to the insertion of a duplicated copy of NMB1423 (NMB0459) in MC58 presumably coding for a Fic (filamentation induced by cAMP)-like protein (SI Fig. 5). Our results suggest that recombination at dRS3 elements might not only result in gene loss as has already been demonstrated for fetA (25), opcA (26), and porA (27), but also in gene insertions and chromosomal rearrangements.

Of note, it has recently been shown that the phage Nf1 integrates into the most abundant subclass of dRS3 elements called herein dRS3/Nf1 (15, 16) (Table 1) by the action of the phage-encoded transposase/integrase (also termed ISNgoIII in Fig. 3) (28). Therefore, besides recA-dependent homologous recombination, also ISNgoIII might catalyze the recombination between different dRS3/Nf1 elements resulting in permanent genomic changes such as the observed translocations or deletions of dRS3/Nf1-enclosed genes. Because many of these genes code for surface proteins involved in the interaction of bacteria with host cells (12), their chromosomal translocation could in turn lead to the observed virulence differences between hypervirulent lineages and carriage isolates because of an altered expression of the affected genes. Future studies should therefore assess whether gene or protein expression profiles are modulated by such chromosomal translocations.

Fig. 3.
IS profile of the sequenced neisserial genomes. For each IS element, the TBLASTN score ratios of the best hit in the genome versus the self-hit is coded in grayscale, with black indicating a perfect hit and white a lack of a homologous sequence in the ...

IS1655 and Speciation of N. meningitidis.

Computational analyses of the IS content by TBLASTN comparisons revealed that N. meningitidis can be separated from the other two sequenced neisserial species based on the respective IS repertoires (Fig. 3). Therefore, speciation events in Neisseria were accompanied by the acquisition of certain IS elements. In fact, we showed by DNA/DNA hybridization studies that IS1655 (IS30 family) is specific to N. meningitidis (SI Table 3) and does not have any homologs in the sequenced genomes of Neisseria lactamica and Neisseria gonorrhoeae (Fig. 3). Based on whole-genome alignments, IS1655 was also found to be involved in the formation of large composite transposons mobilizing ≈30 kb of chromosomal DNA in the genomes of α153 and MC58, respectively (designated T2 in Fig. 2). There was also not a single instance of an IS1655 element that has the same chromosomal location in all six strains, suggesting a high mobility of meningococcal IS1655.

In face of the high selective pressure for inactivation of transposases in the meningococcal genomes (29), the low number of inactivating mutations (SI Fig. 6) together with the inferred high mobility of IS1655 provide evidence for a quite recent infection of the meningococcal genomes with this element. This conclusion is also supported by the remarkably low intergenomic and intragenomic sequence diversity of IS1655 (SI Table 4) that was shown not to be the result of gene conversion events (30). Taken together, these data indicate an evolutionarily quite recent population bottleneck because of, e.g., a change in the lifestyle of N. meningitidis or its ancestor such as specialization to novel human-related niches and/or mode of transmission.

Genome-Based Reconstruction of Meningococcal Phylogeny.

In Neisseria spp., phylogenetic reconstructions based on sequence comparisons of single genes were shown to result in conflicting tree topologies because of frequent intraspecies and interspecies homologous recombination (31, 32). Accordingly, a phylogenetic reconstruction based on shared gene content also indicated an extensive horizontal gene flow between the genomes as can be inferred from the network-like structure in Fig. 4A. However, the constitutively unencapsulated cnl strain α14 resided on a common split with N. gonorrhoeae and N. lactamica, indicating that among the meningococcal strains compared α14 is closest to N. gonorrhoeae and N. lactamica despite the inferred high rate of horizontal gene transfer (HGT). Also, with respect to its IS profile, α14 is the meningococcal strain most similar to N. lactamica and N. gonorrhoeae, respectively, among the genomes compared (Fig. 3).

Fig. 4.
Genome-based neisserial phylogeny using the neighbor-net reconstruction method. (A) Phylogeny based on the distribution of 2,633 genes with COG annotation in the sequenced neisserial genomes. (B) Phylogeny of the six completely sequenced neisserial genomes ...

In contrast to phylogenetic analyses based on shared gene content, intrachromosomal rearrangements are not subject to horizontal transfer and therefore allow for a phylogenetic reconstruction even in the face of frequent interstrain recombination (33). In fact, N. meningitidis has a high number of repeated sequences of all kinds (34), which can readily serve as target sites for recombination events resulting in intrachromosomal rearrangements as outlined above. Again, a neighbor-net reconstruction based on genome rearrangement (Fig. 4B) and breakpoint distances (data not shown) also suggests that, among the genomes compared, α14 is the meningococcal strain closest to N. gonorrhoeae and N. lactamica.

Taken together, these results provide strong evidence that strain α14 resembles an unencapsulated common ancestor along with N. gonorrhoeae and N. lactamica.

On the Evolution of Virulence in N. meningitidis.

The only factor that was clearly associated with a pathogenic phenotype in N. meningitidis is the polysaccharide capsule (8). The cps locus required for the synthesis of the polysaccharide capsule consists of five regions termed region A to region E (SI Fig. 7) (9). Although regions E and D might belong to the neisserial core genome because they can be found in many other Neisseria spp., regions A–C containing the genes required for capsule synthesis, modification, and transport, respectively, can only be found in the encapsulated meningococcal strains. In line with an acquisition via HGT from other species, region A and C have a lower GC content when compared with the rest of the genome. Also the ctrABCD (NMA0195–0198) genes of region C and the lipAB (NMA0185–0186) genes of region B in N. meningitidis Z2491 are highly similar in sequence and operon organization to the hexABCD (PMO0778–0781) and phyAB (PMO0772–0773) genes in the Pasteurella multocida genome (GenBank AE004439), respectively (SI Fig. 8). These results are in line with previous observations of HGT from Haemophilus influenzae being also a member of the Pasteurellaceae and inhabitant of the human airways to N. meningitidis (35). Therefore, the encapsulated and thus potentially pathogenic strains of N. meningitidis might have evolved from an unencapsulated ancestor by horizontal acquisition of the cps locus from other bacteria residing in the human nasopharynx (36).

Conclusion and Outlook.

Our results from whole-genome comparisons suggest an origin of the encapsulated meningococcal strains from an unencapsulated common ancestor with N. gonorrhoeae and N. lactamica. Historically, meningococcal disease is believed to have emerged quite recently with definitive descriptions dating only from 1805 in Europe and North America and 1905 in Africa (37). The genes required for capsule synthesis were acquired from other bacterial species residing in the human nasopharynx via HGT only very recently, and our data suggest that the sources were members of the family Pasteurellaceae. This proposed recent emergence of N. meningitidis in turn explains the highly similar genomic makeups of disease and carriage isolates. With the phage Nf1 possibly modulating the virulence of the infected strains, differences in the pathogenic potential between carriage and disease isolates might thus be influenced by small genetic differences in genes from the core genome. One prime candidate would be variation in the repeat tracts of phase variable genes associated with host cell interactions (12), which will be detectable as single nucleotide polymorphisms (SNPs) in larger collections of genome sequences from freshly isolated carriage and disease strains. Whole-genome association mapping of resulting SNP haplotypes with the propensity of a strain to cause disease might reveal the anticipated genetic differences. Novel high-throughput sequencing technologies (38) will enable the sequencing of the large number of further strains and species required (39) to test the proposed evolutionary scenario and the hypotheses on the emergence of virulence in N. meningitidis.

Materials and Methods

Genome Sequencing and Assembly.

The three sequenced N. meningitidis strains α14, α153, and α275 were chosen from a collection of 830 meningococcal isolates obtained during a carriage study in 8,000 children and young adults in Bavaria, Germany, in 1999/2000 (3). Genome sequences were generated by whole-genome shotgun sequencing. The single contig of strain α14 was assembled from 32,059 reads (giving a 9.38× coverage) from pGEM-Teasy (Promega) clones with 2.0- to 3.0-kb inserts. The draft genomes of strains α153 and α275 were sequenced to 8× coverage from 29,283 reads for strain α275 and from 26,630 reads for strain α153, respectively, and the resulting nonoverlapping contigs were pasted together into a pseudochromosome in random order with the sequence 5′-CTAGCTAGCTAG-3′ used as spacer that generates a stop codon in all six reading frames.

Genome Annotation.

Automated annotations of the assembled genome sequences were carried out with the genome annotation system GeneDB2 (40), followed by manual curation for strain α14. For the comparative analysis of IS content, the genome sequences were searched with TBLASTN (41) using the neisserial ISs deposited in the ISfinder database (42) as query sequences. Based on the score ratio of the best hit in the genome versus the self hit, ISs and strains were clustered based on the correlation distance using Cluster 3.0 (43).

Whole-Genome Alignments.

The annotated genomes of N. meningitidis strains Z2491 (AL157959) (13), MC58 (AE002098) (14), and FAM18 (AM421808.3) (12) were used for whole-genome alignments. Pairwise BLASTN alignments of genome sequences were visualized by using the Artemis Comparison Tool Release 5 (44). Multiple whole-genome alignments were performed by using Mauve 2.0, which has been particularly designed for the identification and alignment of conserved genomic DNA in the presence of rearrangements and HGT (33).

Estimation of Core Genome and Pangenome Sizes.

Orthologous proteins were operationally identified as reciprocal best matches in BLASTP and TBLASTN comparisons, respectively. A coding sequence was considered to be orthologous to the query sequence if there was >50% amino acid sequence identity over at least 50% of the query sequence length. The core and pangenome sizes were estimated by nonlinear regression as described in ref. 18. For analyzing the meningococcal pathogenome, the results of BLASTP comparisons were combined with genomic BLASTN alignments to asses the synteny of putative orthologs and to reduce the number of genes falsely detected as pathogen-specific because of a missing annotation in the carriage strains.

Dot Blot Hybridization.

For DNA/DNA dot blot hybridizations, either 20 μl of suspensions of 1010 colony forming units per ml or 200 ng of chromosomal DNA were spotted onto nylon membranes (Macherey-Nagel). Dot blot hybridizations were performed by using digoxigenin-labeled probes as described in ref. 45. The following oligonucleotides (Sigma–Aldrich) were used to generate an IS1655 probe by PCR: HC277R (5′-CGC CAA GAC AAA AGC AAC GG-3′) and HC273 (5′-ATA CGC CAC AAT AGC TCA GC-3′).

Genome-Based Phylogenetic Analyses.

For phylogenetic analyses, the genome sequences of N. gonorrhoeae FA1090 (AE004969.1) and N. lactamica (www.sanger.ac.uk/Projects/Microbes/) were used as outgroups.

SPRING (46) was used for the calculation of rearrangement and breakpoint distances, respectively, from the order of locally collinear blocks (LCBs) being present in all genomes compared. Based on the resulting distance matrices, SplitsTree4 (47) was subsequently used for a neighbor-net reconstruction (48). The robustness of the resulting network topology was confirmed with respect to variation of the parameter settings and the number of genomes compared. In addition, a jackknife resampling method was applied that consisted of the random omission of 10% of the LCBs from each of the LCB order files compared as generated by SPRING.

For the construction of a neighbor-net based on the differential distribution of COGs in the neisserial genomes, genes with COG assignment were selected based either on their primary annotation or on PSI-BLAST hits in the COG database with an E value cutoff of 1E-10. All-against-all reciprocal BLASTP comparisons were performed and a corresponding presence-absence-matrix based on the differential distribution of 2,633 COG annotated proteins was generated. For each genome pair, a genome distance based on Dollo parsimony (49) was computed by using SplitsTree4 and a network was generated based on the neighbor-net algorithm. To assess the statistical robustness of the resulting network, a bootstrap analysis was performed with 10,000 resampling steps.

Supplementary Material

Supporting Information:


We gratefully acknowledge Julian Parkhill for the permission to use the N. lactamica genome sequence for the phylogenetic comparisons, Martin Maiden for helpful critique on phylogenetic inference in N. meningitidis, and Gabriele Gerlach for critical reading of the manuscript. The work on the meningococcal genomes was supported by the Bundesministerium für Bildung und Forschung in the context of the PathoGenoMik and PathoGenoMik-Plus funding initiative.


The authors declare no conflict of interest.

Data deposition: The sequences reported in this paper have been deposited in the DNA Data Base in Japan/European Molecular Biology Laboratory/GenBank databases [accession nos. AM889136 (α14), AM889137 (α153), and AM889138 (α275)].

This article contains supporting information online at www.pnas.org/cgi/content/full/0800151105/DC1.


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