The role of Klebsiella pneumoniae rmpA in capsular polysaccharide synthesis and virulence revisited

Hsu, Chun-Ru; Lin, Tzu‐Lung; Chen, You-Ci; Chou, Huei‐Chi; Wang, Jann-Tay

doi:10.1099/mic.0.050336-0

Cited by 188 publications

(189 citation statements)

References 43 publications

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“…For example, increased glucose concentrations result in the upregulation of capsule production though RmpA, while relatively high extracellular iron concentrations result in the downregulation of capsule production. In fact, 55 to 100% of HV K. pneumoniae strains express at least one copy of rmpA or rmpA2, compared to 7 to 20% of non-HV K. pneumoniae strains (47,214). These genes positively regulate the cps locus at the transcriptional level, resulting in the hypercapsule phenotype (202,(215)(216)(217).…”

Section: Capsulementioning

confidence: 99%

“…These genes positively regulate the cps locus at the transcriptional level, resulting in the hypercapsule phenotype (202,(215)(216)(217). However, not all of these genes must be upregulated or even present concurrently (214,216,218,219). Hypercapsule production can be triggered in the absence of rmpA or rmpA2 by chromosomal mucoviscosity-associated gene A (magA) (41).…”

Section: Capsulementioning

confidence: 99%

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Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,295

1,345

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SUMMARYKlebsiella pneumoniaecauses a wide range of infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Historically,K. pneumoniaehas caused serious infection primarily in immunocompromised individuals, but the recent emergence and spread of hypervirulent strains have broadened the number of people susceptible to infections to include those who are healthy and immunosufficient. Furthermore,K. pneumoniaestrains have become increasingly resistant to antibiotics, rendering infection by these strains very challenging to treat. The emergence of hypervirulent and antibiotic-resistant strains has driven a number of recent studies. Work has described the worldwide spread of one drug-resistant strain and a host defense axis, interleukin-17 (IL-17), that is important for controlling infection. Four factors, capsule, lipopolysaccharide, fimbriae, and siderophores, have been well studied and are important for virulence in at least one infection model. Several other factors have been less well characterized but are also important in at least one infection model. However, there is a significant amount of heterogeneity inK. pneumoniaestrains, and not every factor plays the same critical role in all virulentKlebsiellastrains. Recent studies have identified additionalK. pneumoniaevirulence factors and led to more insights about factors important for the growth of this pathogen at a variety of tissue sites. Many of these genes encode proteins that function in metabolism and the regulation of transcription. However, much work is left to be done in characterizing these newly discovered factors, understanding how infections differ between healthy and immunocompromised patients, and identifying attractive bacterial or host targets for treating these infections.

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Section: Capsulementioning

confidence: 99%

Section: Capsulementioning

confidence: 99%

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,295

1,345

View full text Add to dashboard Cite

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“…Genes that encode a number of virulence factors, including those that are responsible for the hypermucoviscous phenotype (RmpA) and the siderophores (SP) aerobactin and salmochelin, are located on a large, 200-to 220-kb virulence plasmid that is not present in most cKP strains (16)(17)(18). Since the hypermucoviscous phenotype (which is probably due to increased capsule production) (reviewed in reference 2) was the initial defining trait of hvKP strains, it has received significant attention as a virulence factor and, despite conflicting data (2,(19)(20)(21), likely contributes to the increased pathogenicity. Other studies have identified factors that contribute to the virulence of hvKP, but these factors or properties are often present in cKP strains.…”

mentioning

confidence: 99%

Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae

et al. 2014

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f Hypervirulent (hypermucoviscous) Klebsiella pneumoniae (hvKP) strains are an emerging variant of "classical" K. pneumoniae (cKP) that cause organ and life-threatening infection in healthy individuals. An understanding of hvKP-specific virulence mechanisms that enabled evolution from cKP is limited. Observations by our group and previously published molecular epidemiologic data led us to hypothesize that hvKP strains produced more siderophores than cKP strains and that this trait enhanced hvKP virulence. Quantitative analysis of 12 hvKP strains in iron-poor minimal medium or human ascites fluid showed a significant and distinguishing 6-to 10-fold increase in siderophore production compared to that for 14 cKP strains. Surprisingly, highpressure liquid chromatography (HPLC)-mass spectrometry and characterization of the hvKP strains hvKP1, A1142, and A1365 and their isogenic aerobactin-deficient (⌬iucA) derivatives established that aerobactin accounted for the overwhelming majority of increased siderophore production and that this was not due to gene copy number. Further, aerobactin was the primary factor in conditioned medium that enhanced the growth/survival of hvKP1 in human ascites fluid. Importantly the ex vivo growth/ survival of hvKP1 ⌬iucA was significantly less than that of hvKP1 in human ascites fluid, and the survival of outbred CD1 mice challenged subcutaneously or intraperitoneally with hvKP1 was significantly less than that of mice challenged with hvKP1 ⌬iucA. The lowest subcutaneous and intraperitoneal challenge inocula of 3 ؋ 10 2 and 3.2 ؋ 10 1 CFU, respectively, resulted in 100% mortality, demonstrating the virulence of hvKP1 and its ability to cause infection at a low dose. These data strongly support that aerobactin accounts for increased siderophore production in hvKP compared to cKP (a potential defining trait) and is an important virulence factor.

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“…A distinguishing factor of many hvKP strains is its hypermucoviscous phenotype (14). This phenotype has been established to be due to increased capsular polysaccharide (e.g., K1, K2 et al) production (15)(16)(17). Although K1 and K2 capsular serotypes have been shown to contribute to the virulence of cKP strains in a mouse IP challenge model (18), increased expression of the K2 capsule (hypermucoviscous phenotype) has been shown to add to the virulence of hvKP in a mouse IP challenge model (15).…”

mentioning

confidence: 99%

Aerobactin, but Not Yersiniabactin, Salmochelin, or Enterobactin, Enables the Growth/Survival of Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae Ex Vivo and In Vivo

et al. 2015

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The siderophore aerobactin is the dominant siderophore produced by hypervirulent Klebsiella pneumoniae (hvKP) and was previously shown to be a major virulence factor in systemic infection. However, strains of hvKP commonly produce the additional siderophores yersiniabactin, salmochelin, and enterobactin. The roles of these siderophores in hvKP infection have not been optimally defined. To that end, site-specific gene disruptions were created in hvKP1 (wild type), resulting in the generation of hvKP1⌬iucA (aerobactin deficient), hvKP1⌬iroB (salmochelin deficient), hvKP1⌬entB (enterobactin and salmochelin deficient), hvKP1⌬irp2 (yersiniabactin deficient), and hvKP1⌬entB⌬irp2 (enterobactin, salmochelin, and yersiniabactin deficient). The growth/survival of these constructs was compared to that of their wild-type parent hvKP1 ex vivo in human ascites fluid, human serum, and human urine and in vivo in mouse systemic infection and pulmonary challenge models. Interestingly, in contrast to aerobactin, the inability to produce enterobactin, salmochelin, or yersiniabactin individually or in combination did not decrease the ex vivo growth/survival in human ascites or serum or decrease virulence in the in vivo infection models. Surprisingly, none of the siderophores increased growth in human urine. In human ascites fluid supplemented with exogenous siderophores, siderophores increased the growth of hvKP1⌬iucA, with the relative activity being enterobactin > aerobactin > yersiniabactin > salmochelin, suggesting that the contribution of aerobactin to virulence is dependent on both innate biologic activity and quantity produced. Taken together, these data confirm and extend a role for aerobactin as a critical virulence factor for hvKP. Since it appears that aerobactin production is a defining trait of hvKP strains, this factor is a potential antivirulence target. In the ongoing chess match between microbial pathogens and the human host, the pathogens as of late seem to be gaining the upper hand. Klebsiella pneumoniae is proving to be especially problematic and has evolved into two distinct epidemiologically and clinically defined pathotypes.The first and best-known pathotype, best termed "classical" K. pneumoniae (cKP), is presently responsible for the majority of K. pneumoniae infections in Western countries, which primarily occur in hospitals and long-term-care facilities (1). Importantly, cKP strains have received increased notoriety due to their propensity for acquiring antimicrobial resistance determinants, primarily carbapenemases, that make treatment challenging. The spread of New Delhi metallo-␤-lactamase (NDM-1)-containing strains from India that are associated with medical tourism and, more recently, the extremely drug-resistant K. pneumoniae (XDR-KP) outbreak at the Clinical Center Hospital on the NIH campus have captured the attention of physicians, scientists, and the press (2, 3). XDR-KP is spreading globally and is primarily responsible for the increase in infections due to carbapenem-resistant bacteria in the U...

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The role of Klebsiella pneumoniae rmpA in capsular polysaccharide synthesis and virulence revisited

Cited by 188 publications

References 43 publications

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae

Aerobactin, but Not Yersiniabactin, Salmochelin, or Enterobactin, Enables the Growth/Survival of Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae Ex Vivo and In Vivo

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