RESUMO
BACKGROUND: Colibactin 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 Taiwan. METHODOLOGY/PRINCIPAL FINDINGS: At 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. CONCLUSIONS: Our 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.
Assuntos
Infecções por Klebsiella/complicações , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/genética , Família Multigênica , Mutagênicos/metabolismo , Peptídeos/genética , Animais , Linhagem Celular , Dano ao DNA , Deleção de Genes , Genes Bacterianos , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/genética , Klebsiella pneumoniae/fisiologia , Fígado/microbiologia , Abscesso Hepático Piogênico/etiologia , Abscesso Hepático Piogênico/genética , Abscesso Hepático Piogênico/microbiologia , Camundongos Endogâmicos BALB C , Policetídeos , Taiwan/epidemiologiaRESUMO
Mucoviscosity-associated gene A (magA) of Klebsiella pneumoniae contributes to K1 capsular polysaccharide (CPS) biosynthesis. Based on sequence homology and gene alignment, the magA gene has been predicted to encode a Wzy-type CPS polymerase. Sequence alignment with the Wzy_C and RfaL protein families (which catalyze CPS or lipopolysaccharide (LPS) biosynthesis) and topological analysis has suggested that eight highly conserved residues, including G308, G310, G334, G337, R290, P305, H323, and N324, were located in a hypothetical loop region. Therefore, we used site-directed mutagenesis to study the role of these residues in CPS production, and to observe the consequent phenotypes such as mucoviscosity, serum and phagocytosis resistance, and virulence (as assessed in mice) in pyogenic liver abscess strain NTUH-K2044. Alanine substitutions at R290 or H323 abolished all of these properties. The G308A mutant was severely impaired for these functions. The G334A mutant remained mucoid with decreased CPS production, but its virulence was significantly reduced in vivo. No phenotypic change was observed for strains harboring magA G310A, G337A, P305A, or N324A mutations. Therefore, R290, G308, H323, and G334 are functionally important residues of the MagA (Wzy) protein of K. pneumoniae NTUH-K2044, capsular type K1. These amino acids are also likely to be important for the function of Wzy in other capsular types in K. pneumoniae and other species bearing Wzy_C family proteins.
Assuntos
Alanina , Cápsulas Bacterianas , Proteínas de Bactérias , Klebsiella pneumoniae , Alanina/química , Alanina/genética , Substituição de Aminoácidos , Animais , Antígenos de Bactérias , Cápsulas Bacterianas/genética , Cápsulas Bacterianas/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Abscesso Hepático Piogênico/genética , Camundongos , Mutagênese Sítio-Dirigida , Fagocitose , Polissacarídeos Bacterianos , Alinhamento de Sequência , Relação Estrutura-AtividadeRESUMO
Papillon Lefèvre syndrome is a rare disease characterized by skin lesions caused by palmar-plantar hyperkeratosis, and severe periodontal destruction involving both the primary and permanent dentitions. It is transmitted as an autosomal recessive condition and consanguinity of parents is evident in about one-third of cases. Pyogenic liver abscess is an increasingly recognized complication. We report a new case of this association and review the current literature.
