Abstract
ABSTRACT
Typical Klebsiella pneumoniae is an opportunistic pathogen, which mostly affects those with weakened immune systems and tends to cause nosocomial infections. A subset of hypervirulent K. pneumoniae serotypes with elevated production of capsule polysaccharide can affect previously healthy persons and cause life-threatening community-acquired infections, such as pyogenic liver abscess, meningitis, necrotizing fasciitis, endophthalmitis and severe pneumonia. K. pneumoniae utilizes a variety of virulence factors, especially capsule polysaccharide, lipopolysaccharide, fimbriae, outer membrane proteins and determinants for iron acquisition and nitrogen source utilization, for survival and immune evasion during infection. This article aims to present the state-of-the-art understanding of the molecular pathogenesis of K. pneumoniae.
References
- 1 . Klebsiella spp. as nosocomial pathogens: epidemiology, taxonomy, typing methods, and pathogenicity factors. Clin. Microbiol. Rev. 11(4), 589–603 (1998).
- 2 . Role of type 1 and type 3 fimbriae in Klebsiella pneumoniae biofilm formation. BMC Microbiol. 10, 179 (2010).
- 3 . Klebsiella pneumoniae MrkD-mediated biofilm formation on extracellular matrix- and collagen-coated surfaces. Microbiology 149(Pt 9), 2397–2405 (2003).
- 4 International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections. Ann. Intern. Med. 140(1), 26–32 (2004).
- 5 Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect. Dis. 13(9), 785–796 (2013).
- 6 Capsular polysaccharide synthesis regions in Klebsiella pneumoniae serotype K57 and a new capsular serotype. J. Clin. Microbiol. 46(7), 2231–2240 (2008).
- 7 Capsular types of Klebsiella pneumoniae revisited by wzc sequencing. PLoS ONE 8(12), e80670 (2013).
- 8 . Isolation of a bacteriophage specific for a new capsular type of Klebsiella pneumoniae and characterization of its polysaccharide depolymerase. PLoS ONE 8(8), e70092 (2013).
- 9 . Hypervirulent Klebsiella pneumoniae: the next superbug? Future Microbiol. 7(6), 669–671 (2012).
- 10 . Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: a new and dangerous breed. Virulence 4(2), 107–118 (2013).
- 11 Assessment of hypermucoviscosity as a virulence factor for experimental Klebsiella pneumoniae infections: comparative virulence analysis with hypermucoviscosity-negative strain. BMC Microbiol. 11, 50 (2011).
- 12 . Klebsiella pneumoniae liver abscess: a new invasive syndrome. Lancet Infect. Dis. 12(11), 881–887 (2012).
- 13 . Conserved organization in the cps gene clusters for expression of Escherichia coli group 1 K antigens: relationship to the colanic acid biosynthesis locus and the cps genes from Klebsiella pneumoniae. J. Bacteriol. 181(7), 2307–2313 (1999).
- 14 . Biosynthesis and assembly of capsular polysaccharides in Escherichia coli. Annu. Rev. Biochem. 75, 39–68 (2006).
- 15 Genetic diversity of capsular polysaccharide biosynthesis in Klebsiella pneumoniae clinical isolates. Microbiology 155(Pt 12), 4170–4183 (2009).
- 16 Pyrosequencing-based analysis reveals a novel capsular gene cluster in a KPC-producing Klebsiella pneumoniae clinical isolate identified in Brazil. BMC Microbiol. 12, 173 (2012).
- 17 . PCR characterization and typing of Klebsiella pneumoniae using capsular type-specific, variable number tandem repeat and virulence gene targets. J. Med. Microbiol. 59(Pt 5), 541–547 (2010).
- 18 PCR-Based Identification of Klebsiella pneumoniae subsp. rhinoscleromatis, the agent of rhinoscleroma. PLoS Negl. Trop. Dis. 5(5), e1052 (2011).
- 19 wzi gene sequencing, a rapid method for determination of capsular type for Klebsiella strains. J. Clin. Microbiol. 51(12), 4073–4078 (2013).
- 20 Amino acid substitutions of MagA in Klebsiella pneumoniae affect the biosynthesis of the capsular polysaccharide. PLoS ONE 7(10), e46783 (2012).
- 21 Revisiting the importance of virulence determinant magA and its surrounding genes in Klebsiella pneumoniae causing pyogenic liver abscesses: exact role in serotype K1 capsule formation. J. Infect. Dis. 201(8), 1259–1267 (2010).
- 22 . Contribution of mucoviscosity-associated gene A (magA) to virulence in experimental Klebsiella pneumoniae endophthalmitis. Invest. Ophthalmol. Vis. Sci. 52(9), 6860–6866 (2011).
- 23 . RmpA2, an activator of capsule biosynthesis in Klebsiella pneumoniae CG43, regulates K2 cps gene expression at the transcriptional level. J. Bacteriol. 185(3), 788–800 (2003).
- 24 . RmpA regulation of capsular polysaccharide biosynthesis in Klebsiella pneumoniae CG43. J. Bacteriol. 192(12), 3144–3158 (2010).
- 25 . The role of Klebsiella pneumoniae rmpA in capsular polysaccharide synthesis and virulence revisited. Microbiology 157(Pt 12), 3446–3457 (2011).
- 26 . Molecular analysis of the contribution of the capsular polysaccharide and the lipopolysaccharide O side chain to the virulence of Klebsiella pneumoniae in a murine model of pneumonia. Infect. Immun. 70(5), 2583–2590 (2002).
- 27 . Use of a Dictyostelium model for isolation of genetic loci associated with phagocytosis and virulence in Klebsiella pneumoniae. Infect. Immun. 79(3), 997–1006 (2011).
- 28 Capsule impedes adhesion to and invasion of epithelial cells by Klebsiella pneumoniae. Infect. Immun. 68(12), 6744–6749 (2000).
- 29 Roles of capsule and lipopolysaccharide O antigen in interactions of human monocyte-derived dendritic cells and Klebsiella pneumoniae. Infect. Immun. 78(1), 210–219 (2010).
- 30 . Contribution of fucose-containing capsules in Klebsiella pneumoniae to bacterial virulence in mice. Exp. Biol. Med. (Maywood) 233(1), 64–70 (2008).
- 31 Structure and immunological characterization of the capsular polysaccharide of a pyrogenic liver abscess caused by Klebsiella pneumoniae: activation of macrophages through Toll-like receptor 4. J. Biol. Chem. 286(24), 21041–21051 (2011).
- 32 . Mutation in fucose synthesis gene of Klebsiella pneumoniae affects capsule composition and virulence in mice. Exp. Biol. Med. (Maywood) 236(2), 219–226 (2011).
- 33 . Comparison of the host responses to wild-type and cpsB mutant Klebsiella pneumoniae infections. Infect. Immun. 74(9), 5402–5407 (2006).
- 34 . The uptake of a Klebsiella pneumoniae capsule polysaccharide mutant triggers an inflammatory response by human airway epithelial cells. Microbiology 152(Pt 2), 555–566 (2006).
- 35 Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1-dependent manner. Cell Microbiol. 13(1), 135–153 (2011).
- 36 . Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. Microbiology 154(Pt 12), 3877–3886 (2008).
- 37 . Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect. Immun. 72(12), 7107–7114 (2004).
- 38 . Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276(8), 5707–5713 (2001).
- 39 Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am. J. Respir. Cell. Mol. Biol. 22(6), 714–721 (2000).
- 40 Klebsiella pneumoniae capsule polysaccharide impedes the expression of beta-defensins by airway epithelial cells. Infect. Immun. 78(3), 1135–1146 (2010).
- 41 Klebsiella pneumoniae lipopolysaccharide O typing: revision of prototype strains and O-group distribution among clinical isolates from different sources and countries. J. Clin. Microbiol. 37(1), 56–62 (1999).
- 42 Lipopolysaccharide O1 antigen contributes to the virulence in Klebsiella pneumoniae causing pyogenic liver abscess. PLoS ONE 7(3), e33155 (2012).
- 43 . Cloning and sequencing of the Klebsiella pneumoniae O5 wb gene cluster and its role in pathogenesis. Infect. Immun. 68(5), 2435–2440 (2000).
- 44 . Capsular polysaccharide is a major complement resistance factor in lipopolysaccharide O side chain-deficient Klebsiella pneumoniae clinical isolates. Infect. Immun. 68(2), 953–955 (2000).
- 45 Role of bacterial surface structures on the interaction of Klebsiella pneumoniae with phagocytes. PLoS ONE 8(2), e56847 (2013).
- 46 The Klebsiella pneumoniae O antigen contributes to bacteremia and lethality during murine pneumonia. Infect. Immun. 72(3), 1423–1430 (2004).
- 47 Surfactant protein D binds selectively to Klebsiella pneumoniae lipopolysaccharides containing mannose-rich O-antigens. J. Immunol. 169(6), 3267–3274 (2002).
- 48 A second outer-core region in Klebsiella pneumoniae lipopolysaccharide. J. Bacteriol. 187(12), 4198–4206 (2005).
- 49 A second galacturonic acid transferase is required for core lipopolysaccharide biosynthesis and complete capsule association with the cell surface in Klebsiella pneumoniae. J. Bacteriol. 189(3), 1128–1137 (2007).
- 50 The Klebsiella pneumoniae wabG gene: role in biosynthesis of the core lipopolysaccharide and virulence. J. Bacteriol. 185(24), 7213–7221 (2003).
- 51 The major surface-associated saccharides of Klebsiella pneumoniae contribute to host cell association. PLoS ONE 3(11), e3817 (2008).
- 52 Genome sequencing and comparative analysis of Klebsiella pneumoniae NTUH-K2044, a strain causing liver abscess and meningitis. J. Bacteriol. 191(14), 4492–4501 (2009).
- 53 . Lipid A modification systems in Gram-negative bacteria. Annu. Rev. Biochem. 76, 295–329 (2007).
- 54 Secondary acylation of Klebsiella pneumoniae lipopolysaccharide contributes to sensitivity to antibacterial peptides. J. Biol. Chem. 282(21), 15569–15577 (2007).
- 55 . Analysis of the networks controlling the antimicrobial-peptide-dependent induction of Klebsiella pneumoniae virulence factors. Infect. Immun. 79(9), 3718–3732 (2011).
- 56 Alveolar macrophages are required for protective pulmonary defenses in murine Klebsiella pneumonia: elimination of alveolar macrophages increases neutrophil recruitment but decreases bacterial clearance and survival. Infect. Immun. 65(4), 1139–1146 (1997).
- 57 . Identification of a conserved chromosomal region encoding Klebsiella pneumoniae type 1 and type 3 fimbriae and assessment of the role of fimbriae in pathogenicity. Infect. Immun. 77(11), 5016–5024 (2009).
- 58 . Regulation of the Klebsiella pneumoniae Kpc fimbriae by the site-specific recombinase KpcI. Microbiology 156(Pt 7), 1983–1992 (2010).
- 59 . A new fimbrial antigen harbored by CAZ-5/SHV-4-producing Klebsiella pneumoniae strains involved in nosocomial infections. Infect. Immun. 64(6), 2266–2273 (1996).
- 60 . A tale of two pili: assembly and function of pili in bacteria. Trends Microbiol. 18(5), 224–232 (2010).
- 61 . FimK regulation on the expression of type 1 fimbriae in Klebsiella pneumoniae CG43S3. Microbiology 159(Pt 7), 1402–1415 (2013).
- 62 . Characterization of Klebsiella pneumoniae type 1 fimbriae by detection of phase variation during colonization and infection and impact on virulence. Infect. Immun. 76(9), 4055–4065 (2008).
- 63 . An invertible element of DNA controls phase variation of type 1 fimbriae of Escherichia coli. Proc. Natl Acad. Sci. USA 82(17), 5724–5727 (1985).
- 64 . Molecular variations in Klebsiella pneumoniae and Escherichia coli FimH affect function and pathogenesis in the urinary tract. Infect. Immun. 76(7), 3346–3356 (2008).
- 65 . Klebsiella pneumoniae and type 3 fimbriae: nosocomial infection, regulation and biofilm formation. Future Microbiol. 7(8), 991–1002 (2012).
- 66 . Klebsiella pneumoniae type 3 fimbriae agglutinate yeast in a mannose-resistant manner. J. Med. Microbiol. 61(Pt 3), 317–322 (2012).
- 67 . Biofilm formation of Klebsiella pneumoniae on urethral catheters requires either type 1 or type 3 fimbriae. FEMS Immunol. Med. Microbiol. 65(2), 350–359 (2012).
- 68 . Role of Klebsiella pneumoniae type 1 and type 3 fimbriae in colonizing silicone tubes implanted into the bladders of mice as a model of catheter-associated urinary tract infections. Infect. Immun. 81(8), 3009–3017 (2013).
- 69 . Dissemination in five French hospitals of Klebsiella pneumoniae serotype K25 harbouring a new transferable enzymatic resistance to third generation cephalosporins and aztreonam. Eur. J. Clin. Microbiol. Infect. Dis. 7(6), 780–782 (1988).
- 70 Klebsiella pneumoniae outer membrane protein A is required to prevent the activation of airway epithelial cells. J. Biol. Chem. 286(12), 9956–9967 (2011).
- 71 . Klebsiella pneumoniae OmpA confers resistance to antimicrobial peptides. Antimicrob. Agents Chemother. 53(1), 298–302 (2009).
- 72 Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence. Antimicrob. Agents Chemother. 55(4), 1485–1493 (2011).
- 73 . OmpK26, a novel porin associated with carbapenem resistance in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 55(10), 4742–4747 (2011).
- 74 . Functional characterization of a novel outer membrane porin KpnO, regulated by PhoBR two-component system in Klebsiella pneumoniae NTUH-K2044. PLoS ONE 7(7), e41505 (2012).
- 75 . Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrob. Agents Chemother. 54(1), 177–183 (2010).
- 76 . A tripartite efflux pump involved in gastrointestinal colonization by Klebsiella pneumoniae confers a tolerance response to inorganic acid. Infect. Immun. 76(10), 4633–4641 (2008).
- 77 . Genomic heterogeneity in Klebsiella pneumoniae strains is associated with primary pyogenic liver abscess and metastatic infection. J. Infect. Dis. 192(1), 117–128 (2005).
- 78 . SitA contributes to the virulence of Klebsiella pneumoniae in a mouse infection model. Microbes Infect. 16(2), 161–170 (2014).
- 79 . Yersiniabactin is a virulence factor for Klebsiella pneumoniae during pulmonary infection. Infect. Immun. 75(3), 1463–1472 (2007).
- 80 . Serum-induced iron-acquisition systems and TonB contribute to virulence in Klebsiella pneumoniae causing primary pyogenic liver abscess. J. Infect. Dis. 197(12), 1717–1727 (2008).
- 81 . Correlation of the virulence of Klebsiella pneumoniae K1 and K2 with the presence of a plasmid encoding aerobactin. Infect. Immun. 54(3), 603–608 (1986).
- 82 A novel PCR-based genotyping scheme for clinical Klebsiella pneumoniae. Future Microbiol. 9(1), 21–32 (2014).
- 83 . Mucosal lipocalin 2 has pro-inflammatory and iron-sequestering effects in response to bacterial enterobactin. PLoS Pathog. 5(10), e1000622 (2009).
- 84 Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2. Infect. Immun. 79(8), 3309–3316 (2011).
- 85 . Interaction of lipocalin 2, transferrin, and siderophores determines the replicative niche of Klebsiella pneumoniae during pneumonia. MBio 3(6), e00224-11 (2012).
- 86 Hypervirulent K. pneumoniae secretes more and more active iron-acquisition molecules than ‘classical’ K. pneumoniae thereby enhancing its virulence. PLoS ONE 6(10), e26734 (2011).
- 87 . Klebsiella aerogenes urease gene cluster: sequence of ureD and demonstration that four accessory genes (ureD, ureE, ureF, and ureG) are involved in nickel metallocenter biosynthesis. J. Bacteriol. 174(13), 4324–4330 (1992).
- 88 . The role of Klebsiella pneumoniae urease in intestinal colonization and resistance to gastrointestinal stress. Res. Microbiol. 157(2), 184–193 (2006).
- 89 . Isolation of a chromosomal region of Klebsiella pneumoniae associated with allantoin metabolism and liver infection. Infect. Immun. 72(7), 3783–3792 (2004).
- 90 Genetic requirements for Klebsiella pneumoniae-induced liver abscess in an oral infection model. Infect. Immun. 77(7), 2657–2671 (2009).