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.
Highlights
Klebsiella pneumoniae is a member of the family Enterobacteriaceae
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, pyogenic liver abscess (PLA), and colorectal cancer (CRC)
35 (16.9%) were regarded as K. pneumoniae-caused liver abscess (KLA) strains as they were obtained from tissueinvasive cases that presented with the formation of liver abscesses, 59 (28.5%) were from cases associated with abscesses at nonhepatic sites, including lesions that occurred as empyema, endophthalmitis, necrotizing fasciitis, septic arthritis, along with lung, epidural, parotid, paraspinal, splenic, renal, prostate, muscle, and deep neck abscesses, and the remaining 113 (54.6%) isolates were obtained from non-abscess-related cases, including pneumonia without abscess, primary peritonitis, cellulitis, biliary tract infection, primary bacteremia with no original infectious foci identifiable, and catheter-related infections
Summary
The ability of K. pneumoniae to cause a wide range of human diseases, from urinary tract infections to life-threatening systemic infections, has attracted increasing attention to the pathogenesis of this bacterium [1,2,3,4]. In 1990s, K. pneumoniae surpassed Escherichia coli as the leading cause of community-acquired pyogenic liver abscess [5]. K. pneumoniae-caused liver abscess (KLA) was recognized by researchers in Taiwan and several other areas since 1986. Distinct from E. coli-caused liver abscess, KLA is generically cryptogenic and is frequently complicated with metastatic lesions to other organs [7,8,9]. 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 Taiwan
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