Population genomics of hypervirulentKlebsiella pneumoniaeclonal group 23 reveals early emergence and rapid global dissemination

Abstract

Since the mid-1980s there have been increasing reports of severe community-acquired pyogenic liver abscess, meningitis and bloodstream infections caused by hypervirulent Klebsiella pneumoniae, predominantly encompassing clonal group (CG) 23 serotype K1 strains. Common features of CG23 include a virulence plasmid associated with iron scavenging and hypermucoidy, and a chromosomal integrative and conjugative element (ICE) encoding the siderophore yersiniabactin and the genotoxin colibactin. Here we investigate the evolutionary history and genomic diversity of CG23 based on comparative analysis of 98 genomes. Contrary to previous reports with more limited samples, we show that CG23 comprises several deep branching sublineages dating back to the 1870s, many of which are associated with distinct chromosomal insertions of ICEs encoding yersiniabactin. We find that most liver abscess isolates (>80%) belong to a dominant sublineage, CG23-I, which emerged in the 1920s following acquisition of ICEKp10 (encoding colibactin in addition to yersiniabactin) and has undergone clonal expansion and global dissemination within the human population. The unique genomic feature of CG23-I is the production of colibactin, which has been reported previously as a promoter of gut colonisation and dissemination to the liver and brain in a mouse model of CG23 K. pneumoniae infection, and has been linked to colorectal cancer. We also identify an antibiotic-resistant subclade of CG23-I associated with sexually-transmitted infections in horses dating back to the 1980s. These data show that hypervirulent CG23 K. pneumoniae was circulating in humans for decades before the liver abscess epidemic was first recognised, and has the capacity to acquire and maintain AMR plasmids. These data provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To further support such studies we present an open access and completely sequenced human liver abscess isolate, SGH10, which is typical of the globally disseminated CG23-I sublineage.

Hypervirulent Klebsiella pneumoniae – clinical and molecular perspectives

“…Genetic inactivation of colibactin synthesis in a pks + K1 ST23 isolate reduced the ability of this hvKP strain to colonize the gut and disseminate to other organs in a murine model of systemic infection as well as to induce cell death in the brain during meningitis [138]. Taken together, colibactin appears to support the colonization and pathogenesis of hvKp and may have contributed to the global spread of CG23 [112], of which K1 ST23 strains are prominent.…”

Klebsiella pneumoniae as a key trafficker of drug resistance genes from environmental to clinically important bacteria

“…Its elevated plasmid load (Fig 2B) suggests K. pneumoniae is particularly permissive for plasmids, meaning it may be more likely to capture plasmid--borne material from diverse donors in varied niches, and to hold on to this material long enough to transmit it to new recipients in human and animal--associated niches (Fig 4). This enhanced permissiveness may reflect a comparatively lower fitness burden of plasmid carriage in K. pneumoniae; a hypothesis supported by a small number of studies showing lower fitness costs for specific AMR plasmids in K. pneumoniae vs E. coli in vitro [82,83], and reports of long--term plasmid maintenance in K. pneumoniae in vivo [64,73,83]. Plasmid--host interactions are complex, and there are many reported examples of specific adaptations of hosts to plasmids (and vice versa) [84,85].…”

“…Clinically important K. pneumoniae lineages have been isolated from specific non--human sources (Fig 3B); e.g. ESBL ST15 in cats and dogs [60][61][62], and hypervirulent ST23 or ST25 in horses, non--human primates and pigs [44,63,64]. Genomic comparisons of K. pneumoniae from diverse sources are rare but show little evidence of segregation between niches: in a global diversity study, 59 bovine isolates were distributed around the species phylogeny comprising mostly human isolates [9]; and a comparison of ESBL isolates from Thai hospitals and a local canal system indicated phylogenetic intermingling [65].…”

Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones ofKlebsiella pneumoniae

“…This possibility is intriguing and could explain the separation of hypervirulence and MDR, by limiting opportunities for horizontal gene transfer between MDR and hypervirulent clones. Isolates representing both clone types have been identified among diverse host--associated niches 31,42,43 but it is not possible to determine any particular ecological preference due to the lack of systematic sampling efforts to--date. An alternative explanation is that the hypervirulent clones are subject to some sort of mechanistic limitation for chromosomal recombination, that in turn limits surface polysaccharide diversity and the acquisition of other chromosomally encoded accessory genes, as have recently shown to be frequently acquired by CG258 strains 44 .…”

“…Taken together these data imply that hypervirulent clones acquire novel plasmids infrequently but can stably maintain them. For example, we recently estimated that the virulence plasmid, which by definition is highly prevalent in these clones, has been maintained for >100 years in CG23 31 . In addition, laboratory passage experiments have shown that hypervirulent strains can maintain MDR plasmids introduced in vitro 29 , and we showed that a horse--associated subclade of CG23 has maintained a single MDR plasmid for at least 20 years 31 .…”