Genotoxic Klebsiella pneumoniae in Taiwan

Abstract

BackgroundColibactin is a nonribosomal peptide-polyketide synthesized by multi-enzyme complexes encoded by the pks gene cluster. Colibactin-producing Escherichia coli have been demonstrated to induce host DNA damage and promote colorectal cancer (CRC) development. In Taiwan, the occurrence of pyogenic liver abscess (PLA) has been suggested to correlate with an increasing risk of CRC, and Klebsiella pneumoniae is the predominant PLA pathogen in TaiwanMethodology/Principal FindingsAt the asn tRNA loci of the newly sequenced K. pneumoniae 1084 genome, we identified a 208-kb genomic island, KPHPI208, of which a module identical to the E. coli pks colibactin gene cluster was recognized. KPHPI208 consists of eight modules, including the colibactin module and the modules predicted to be involved in integration, conjugation, yersiniabactin production, microcin production, and unknown functions. Transient infection of BALB/c normal liver cells with K. pneumoniae 1084 increased the phosphorylation of histone H2AX, indicating the induction of host DNA damage. Colibactin was required for the genotoxicity of K. pneumoniae 1084, as it was diminished by deletion of clbA gene and restored to the wild type level by trans-complementation with a clbA coding plasmid. Besides, BALB/c mice infected with K. pneumoniae 1084 exhibited enhanced DNA damage in the liver parenchymal cells when compared to the isogenic clbA deletion mutant. By PCR detection, the prevalence of pks-positive K. pneumoniae in Taiwan is 25.6%, which is higher than that reported in Europe (3.5%), and is significantly correlated with K1 type, which predominantly accounted for PLA in Taiwan.ConclusionsOur knowledge regarding how bacteria contribute to carcinogenesis has just begun. The identification of genotoxic K. pneumoniae and its genetic components will facilitate future studies to elucidate the molecular basis underlying the link between K. pneumoniae, PLA, and CRC.

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

“…Very few nonribosomal assembly lines in the Enterobacteriaceae have known functional roles. Among those are platforms involved in production of the iron-scavenging siderophores enterobactin and salmochelin, as well as the genotoxin colibactin, which is produced by a hybrid constellation of NRPS, polyketide synthases, and fatty acid synthases (41,42). Surprisingly, the NRPS enzymes of K. oxytoca show little similarity to those of the Enterobacteriaeceae but are closely related to synthases found in Actinomycetes.…”

“…We note with interest that the genetic context for insertion of the tilivalline gene cluster in the enterobacterial core genome is equivalent to the asnW tRNA locus occupied by the polyketide synthase (pks) genotoxic island in E. coli and some isolates of Klebsiella pneumonia (32,42). The pks locus is highly conserved in the E. coli B2 phylogenetic group and an estimated 21% of humans carry colibactin-synthesizing E. coli in their intestinal microbiota (46).…”

When our genome is targeted by pathogenic bacteria

“…A functional pks island generating DSBS has been identified in the genomes of enterobacteria other than E. coli, such as Citrobacter koseri, Enterobacter aerogenes and Klebsiella pneumoniae [24,25]. Mice infected with K. pneumonia pks+ shows DSBs within 1 to 2 days in liver parenchymal cells only in the presence of colibactin [24].…”

“…Mice infected with K. pneumonia pks+ shows DSBs within 1 to 2 days in liver parenchymal cells only in the presence of colibactin [24]. In Taiwanese populations, K. pneumoniae is the most predominant pathogen associated with pyogenic liver abscess, an infection suspected to increase the risk of colorectal cancer development [25]. Additional studies are required to examine this hypothesis.…”

Les infections bactériennes vues du génome eucaryote

“…L'îlot pks présent dans le génome d'entérobactéries autres que E. coli est lui aussi fonctionnel et générateur de cassures double-brin de l'ADN pour des souches de Citrobacter koseri, Enterobacter aerogenes et Klebsiella pneumoniae [18]. Chez la souris, l'infection par K. pneumoniae pks + induit en un à deux jours des cassures double-brin de l'ADN dans les cellules parenchymateuses du foie, ceci à condition que la colibactine soit présente [19]. Or, dans la population de Taïwan, K. pneumoniae est le pathogène prédominant associé à l'abcès à pyogènes du foie, une infection sévère suspectée d'accroître le risque de développer secondairement un cancer colorectal [19].…”