Mapping the Evolution of Hypervirulent Klebsiella pneumoniae

Abstract

Highly invasive, community-acquired Klebsiella pneumoniae infections have recently emerged, resulting in pyogenic liver abscesses. These infections are caused by hypervirulent K. pneumoniae (hvKP) isolates primarily of capsule serotype K1 or K2. Hypervirulent K1 isolates belong to clonal complex 23 (CC23), indicating that this clonal lineage has a specific genetic background conferring hypervirulence. Here, we apply whole-genome sequencing to a collection of K. pneumoniae isolates to characterize the phylogenetic background of hvKP isolates with an emphasis on CC23. Most of the hvKP isolates belonged to CC23 and grouped into a distinct monophyletic clade, revealing that CC23 is a unique clonal lineage, clearly distinct from nonhypervirulent strains. Separate phylogenetic analyses of the CC23 isolates indicated that the CC23 lineage evolved recently by clonal expansion from a single common ancestor. Limited grouping according to geographical origin was observed, suggesting that CC23 has spread globally through multiple international transmissions. Conversely, hypervirulent K2 strains clustered in genetically unrelated groups. Strikingly, homologues of a large virulence plasmid were detected in all hvKP clonal lineages, indicating a key role in K. pneumoniae hypervirulence. The plasmid encodes two siderophores, aerobactin and salmochelin, and RmpA (regulator of the mucoid phenotype); all these factors were found to be restricted to hvKP isolates. Genomic comparisons revealed additional factors specifically associated with CC23. These included a distinct variant of a genomic island encoding yersiniabactin, colibactin, and microcin E492. Furthermore, additional novel genomic regions unique to CC23 were revealed which may also be involved in the increased virulence of this important clonal lineage.

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

“…The CC23 K1 HV K. pneumoniae strains were significantly more closely related to each other than to other K1 strains, indicating that they likely disseminated globally from a distinct variant (235). However, these CC23 K1 HV K. pneumoniae strains were more closely related to the K1 reference strain used in this study than they were to other K. pneumoniae strains (235). It has been suggested that the increased virulence associated with K1 and K2 HV strains may be due to the concurrent carriage of several virulence-associated factors, namely, hypercapsule and the siderophore aerobactin (see below), compared to their presence in other strains (227).…”

“…For example, in a mouse liver abscess model, K1 and K2 strains that lacked a hypercapsule, rmpA, and aerobactin were avirulent (227). In fact, HV CC23 strains all carried the genes for two siderophores as well as RmpA on a large plasmid as well as a genomic island with several differences from other K. pneumoniae strains (235). On the other hand, some work suggests that the presence of the K1/K2 serotypes themselves, rather than hypercapsule, is responsible for increased virulence, as typical capsule-producing K1/K2 strains are not significantly less virulent than hypercapsule-producing K1/K2 strains (229).…”

“…Interestingly, in one study, 27/28 of the K1 HV K. pneumoniae isolates belonged to the same clonal complex (CC23), while the two K2 HV strains examined were genetically unrelated and arose from two distinct clonal lineages (ST25 and ST86) (235). The CC23 K1 HV K. pneumoniae strains were significantly more closely related to each other than to other K1 strains, indicating that they likely disseminated globally from a distinct variant (235). However, these CC23 K1 HV K. pneumoniae strains were more closely related to the K1 reference strain used in this study than they were to other K. pneumoniae strains (235).…”

Rapid and Accurate Determination of Lipopolysaccharide O-Antigen Types in Klebsiella pneumoniae with a Novel PCR-Based O-Genotyping Method

“…The K type and O type of K. pneumoniae both have important clinical and epidemiological significance (8, 12, 13). K1 clonal complex 23 is a newly emerged hypervirulent clade, which causes pyogenic liver abscesses with septic ocular or central nervous system complications (8,14,15). Likewise, O1 is associated with hypervirulent strains that cause pyogenic liver abscess (12).…”

The contribution of capsule polysaccharide genes to virulence of Klebsiella pneumoniae

“…12 However, the study was limited in that it was based on a single strain of each serotype, and thus the relevance of this study's results in regards to other K. pneumoniae strains and serotypes must be explored. In addition, many studies indicate an association between K. pneumoniae serotypes and their severity of infection, 10,14,15 and between production of CPS and antibiotic resistance. 16 Further studies, including serotype switching, are warranted in order to more fully understand the effects of the K antigen or serotype on virulence and other features.…”