Hypervirulent K. Pneumoniae Secretes More and More Active Iron-Acquisition Molecules than “Classical” K. Pneumoniae Thereby Enhancing its Virulence

Russo, Thomas A.; Shon, Alyssa; Beanan, Janet M.; Olson, Ruth; MacDonald, Ulrike; Pomakov, Alexander; Visitacion, Mark P.

doi:10.1371/journal.pone.0026734

Cited by 114 publications

(103 citation statements)

References 57 publications

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“…The discrepancy in the frequency of the rmpA gene between CC65-K2 and GL65-K2 may be explained by the housekeeping genes of MLST, which are located on a chromosome (21), unlike the rmpA gene, which is located on a plasmid. The string test indicated that 66.7% of the GL65-K2 strains had the HV phenotype, which was identified as an important virulence factor for K. pneumoniae in mouse models (31,32). Recent genetic and phenotypic characterizations showed that the genetic background, rather than the capsular serotype, was associated with the virulence of K. pneumoniae (24).…”

Section: Discussionmentioning

confidence: 99%

Molecular Epidemiological Characteristics of Klebsiella pneumoniae Associated with Bacteremia among Patients with Pneumonia

et al. 2015

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e Some important virulence factors have been elucidated in Klebsiella pneumoniae infections. We investigated the relationship between virulence factors and multilocus sequence types (STs) and assessed the risk factors for bacteremia in patients with pneumonia due to K. pneumoniae. From April 2004 through April 2012, a total of 120 K. pneumoniae isolates from patients with pneumonia (23 with bacteremia and 97 without bacteremia) were collected from 10 medical institutions in Japan. Additionally, 10 strains of K. pneumoniae serotype K2 that were isolated >30 years ago were included in this study. These isolates were characterized using multilocus sequence typing (MLST), and the characteristics of their virulence factors, such as hypermucoviscosity phenotype and RmpA and aerobactin production between patients with and without bacteremia, were examined. MLST analysis was performed on the 120 isolates from patients with pneumonia, and some sequence type groups were defined as genetic lineages (GLs). GL65 was more prevalent among patients with bacteremia (21.7%) than in those without bacteremia (7.2%). The majority of the strains with serotype K2 were classified into GL14 or GL65, and rmpA and the gene for aerobactin were present in all GL65-K2 strains but absent in all GL14-K2 strains. In a multivariate analysis, the independent risk factors for bacteremia included GL65 ( K lebsiella pneumoniae is a member of the family Enterobacteriaceae and is one of the most common pathogens causing pneumonia, abscess, bacteremia, and urinary tract infections (1, 2).Over several decades, some virulence factors of K. pneumoniae, including a capsular serotype, the presence of mucoviscosity-associated gene A (magA), and a regulator of mucoid phenotype A (rmpA) gene, have been identified. The strains of serotypes K1 and K2 were found to be virulent in a mouse model (3), and the magA and rmpA genes were found to be associated with hypermucoviscosity (HV), which has an antiphagocytic effect against macrophages and neutrophils (4-6).Clinically, K. pneumoniae was identified as an independent risk factor for mortality in severe community-acquired pneumonia (7). Some studies assessed the relationship between clinical findings and microbiological factors, such as capsular serotype and the presence or absence of rmpA and magA. The site of infections in these studies was mostly intra-abdominal, especially as a liver abscess (5,8). Few studies have focused on respiratory tract infections and investigated the relationship between clinical findings and microbiological factors, including genetic characteristics (9, 10).It is well-known that multilocus sequence typing (MLST), a nucleotide sequence-based genotyping method, is used to characterize genetic relationships among bacterial isolates and to identify and track the global spread of drug-resistant strains (11,12). In order to predict and evaluate bacterial pathogenicity, it is important to first determine the genetic background of the bacteria causing severe infections. Recently, using MLST, s...

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Section: Discussionmentioning

confidence: 99%

Molecular Epidemiological Characteristics of Klebsiella pneumoniae Associated with Bacteremia among Patients with Pneumonia

et al. 2015

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“…To accomplish this goal, most bacteria produce chemically diverse siderophores (20), small-molecule chelators with remarkably high association constants for Fe 3ϩ , that enable them to acquire iron in iron-depleted environments, such as the human host. Interestingly, we have shown that hvKP is characterized by a 6-to 10-fold increase in siderophore activity compared to cKP strains (21,22). Further, and surprisingly, aerobactin accounted for Ͼ90% of the siderophore activity despite the ability of hvKP to produce multiple siderophores (21).…”

mentioning

confidence: 84%

“…The mouse subcutaneous (SQ) challenge and pneumonia models have been described (21,22,27). Animal studies were reviewed and approved by the University at Buffalo-SUNY and Veterans Administration Institutional Animal Care Committee.…”

Section: Methodsmentioning

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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“…When considering these infections, it is important to recall that HV strains are far more likely to cause community-acquired and systemic infections in otherwise healthy individuals, but for the most part, these strains are geographically limited to Taiwan and Southeast Asia. In contrast, classical strains of K. pneumoniae typically cause serious nosocomial infections or UTIs and can be found worldwide (41,(48)(49)(50). While there is a broad overlap of the types of infections caused by classical versus HV strains, some diseases are far more likely to be caused by HV than classical strains.…”

Section: Infections Caused By K Pneumoniaementioning

confidence: 99%

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,366

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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Hypervirulent K. Pneumoniae Secretes More and More Active Iron-Acquisition Molecules than “Classical” K. Pneumoniae Thereby Enhancing its Virulence

Cited by 114 publications

References 57 publications

Molecular Epidemiological Characteristics of Klebsiella pneumoniae Associated with Bacteremia among Patients with Pneumonia

Molecular Epidemiological Characteristics of Klebsiella pneumoniae Associated with Bacteremia among Patients with Pneumonia

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

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

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