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  • fbpase br Methods br Results The Hajj

    2018-11-09


    Methods
    Results The Hajj clone (strain ID: M7124), and six other W ST-11 strains that were sequenced using PacBio provided very high quality reference sequences (Supplementary Table 1), with excellent resolution of capsular genes and other highly repetitive genomic regions. W ST-11 strains in this study were closely related to serogroup C ST-11 strains and clustered into two main groups based on genetic relatedness to the Hajj clone. Out of 270 total strains, 125 (46.3%) were most closely related to the Hajj clone based on antigen-encoding gene profiles (Fig. 2, Supplementary Table 2), presence of recombinant fbpase (Table 1, Supplementary Fig. 1A–D) and whole genome phylogenetic analyses (Fig. 3A–B, Supplementary Fig. 2). We collectively refer to these strains as Cluster 1 (Hajj cluster). All strains in this cluster were isolated during or after the Hajj 2000 epidemic (post-Hajj strains). Remaining 145 strains were more heterogeneous having antigen-encoding gene, phylogenetic and SNP differences within key virulence genes compared to M7124 and were collectively referred to as Cluster 2 strains. This cluster included both historical W ST-11 strains isolated before 2000 (pre-Hajj strains) and post-Hajj strains (2000–2013).
    Discussion In this study, we demonstrate that W ST-11 strains are closely related to serogroup C ST-11 N. meningitidis and likely arose from ancestral capsular switching events. We also demonstrate that the emergence of the Hajj clone in 2000 was caused by a meningococcal strain that was distinct from other circulating serogroup W ST-11 strains. This conclusion is supported by the congruent results from detailed whole genome phylogeny, antigen-encoding gene characterization, and identification of recombinant virulence gene alleles that were unique to the Hajj clone. This study clarifies the recent emergence of serogroup W ST-11 disease globally, which, based on previous limited genetic analyses, appeared to be caused by highly-related strains. Based on these results and those from previous studies (Mayer et al., 2002; Mustapha et al., 2014), we propose a model whereby W ST-11 diverged from a C ST-11 ancestral strain through capsular switching before 1970 (Fig. 4). From the 1970s onward, W ST-11 strains disseminated to cause sporadic disease and case clusters globally (Cluster 2). Cluster 1 strains (Hajj cluster) evolved from sporadic Cluster 2 strains through allelic exchange within four recombinant regions two of which encode FHbp, nitric oxide reductase and nitrite reductase. This model supports global co-circulation of both Cluster 1 (Hajj cluster) and Cluster 2. Sequence variation within the fHbp gene can potentially be used as a marker to identify the Hajj clone and closely related Cluster 1 strains. For example, a study of fHbp gene profiles from 47 endemic W ST-11 strains from 16 African countries isolated from 1980 to 2006 demonstrated that 34% of the strains shared the Hajj clone fHbp allele 9 (Pajon et al., 2011). Also, all W ST-11 strains with the Hajj clone fHbp allele 9 (variant family 1) were isolated after the Hajj 2000 epidemic while fHbp alleles belonging to variant family 2 and 3 were identified both before and after Hajj 2000. These findings are consistent with our results and support our evolutionary model. Since 2001, Hajj related and endemic non Hajj W ST-11 strains have co-circulated across the meningitis belt. In 2002, the largest recorded epidemic of W ST-11 occurred in Burkina Faso with 12,000 cases and 1400 deaths (Koumare et al., 2007). It was generally believed that the Burkina Faso and other African W ST-11 epidemics were caused by direct spread of the Hajj clone. However, three Burkina Faso strains from 2001 to 2002 analyzed in this study all had antigen-encoding gene and other genomic markers consistent with non Hajj-cluster endemic W ST-11 strains. Additionally, Pajon et al (Pajon et al., 2011) reported that 76.5% (17/22) W ST-11 strains from Burkina Faso 2001–2003 had fHbp genotypes associated with endemic non Hajj strains. Epidemics of W ST-11 subsided in the meningitis belt from 2003 to 2009 despite persistence of small case clusters but resurfaced in 2010–2013 (Collard et al., 2010; Novak et al., 2012). Detailed antigenic and genomic characterization of more recent W ST-11 strains from the meningitis belt will be needed to monitor the continued evolution of the Hajj clone and endemic W ST-11 strains.