Identification of Pathogenicity-Associated Loci in Klebsiella pneumoniae from Hospitalized Patients

Martin, Rebekah M.; Cao, Jie; Wu, Weisheng; Zhao, Lili; Manthei, David M; Pirani, Ali; Snitkin, Evan S.; Malani, Preeti N.; Rao, Krishna; Bachman, Michael A.

doi:10.1128/msystems.00015-18

Cited by 49 publications

(67 citation statements)

References 47 publications

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“…Klebsiella virulence is largely attributable to lipopolysaccharide (LPS), pili, a polysaccharide capsule, and siderophores, and these are present in virtually all pathogenic strains ( 2 ). Features specifically linked to hypervirulence include additional siderophores ( 2 , 24 ), tellurite resistance ( 25 , 26 ), and hypermucoviscosity (HMV) ( 2 , 27 , 28 ). Capsule is also linked to hypervirulence, as the majority of hvKp strains have type K1 or K2 ( 24 ), although hv-associated traits have been found in strains with other capsule types ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

The Small Protein RmpD Drives Hypermucoviscosity in Klebsiella pneumoniae

Walker

Treat

Sepúlveda

et al. 2020

mBio

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Klebsiella pneumoniae has a remarkable ability to cause a wide range of human diseases. It is divided into two broad classes: classical strains that are a notable problem in health care settings due to multidrug resistance, and hypervirulent (hv) strains that are historically drug sensitive but able to establish disease in immunocompetent hosts. Alarmingly, there has been an increased frequency of clinical isolates that have both drug resistance and hv-associated genes. One such gene, rmpA, encodes a transcriptional regulator required for maximal capsule (cps) gene expression and confers hypermucoviscosity (HMV). This link has resulted in the assumption that HMV is caused by elevated capsule production. However, we recently reported a new cps regulator, RmpC, and ΔrmpC mutants have reduced cps expression but retain HMV, suggesting that capsule production and HMV may be separable traits. Here, we report the identification of a small protein, RmpD, that is essential for HMV but does not impact capsule. RmpD is 58 residues with a putative N-terminal transmembrane domain and highly positively charged C-terminal half, and it is conserved among other hv K. pneumoniae strains. Expression of rmpD in trans complements both ΔrmpD and ΔrmpA mutants for HMV, suggesting that RmpD is the key driver of this phenotype. The rmpD gene is located between rmpA and rmpC, within an operon regulated by RmpA. These data, combined with our previous work, suggest a model in which the RmpA-associated phenotypes are largely due to RmpA activating the expression of rmpD to produce HMV and rmpC to stimulate cps expression. IMPORTANCE Capsule is a critical virulence factor in Klebsiella pneumoniae, in both antibiotic-resistant classical strains and hypervirulent strains. Hypervirulent strains usually have a hypermucoviscosity (HMV) phenotype that contributes to their heightened virulence capacity, but the production of HMV is not understood. The transcriptional regulator RmpA is required for HMV and also activates capsule gene expression, leading to the assumption that HMV is caused by hyperproduction of capsule. We have identified a new gene (rmpD) required for HMV but not for capsule production. This distinction between HMV and capsule production will promote a better understanding of the mechanisms of hypervirulence, which is in great need given the alarming increase in clinical isolates with both drug resistance and hypervirulence traits.

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Section: Introductionmentioning

confidence: 99%

The Small Protein RmpD Drives Hypermucoviscosity in Klebsiella pneumoniae

Walker

Treat

Sepúlveda

et al. 2020

mBio

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“…We then hypothesized that ter may be required during gut colonization, which precedes infection 2,3 . Exposure to antibiotics was not associated with Kp colonization or subsequent infection in our intensive care unit patient population 1,18 , indicating that Kp must contend with the indigenous microbiota to colonize the gut and cause infection. Previous studies have shown that gut microbiota differs by mouse vendor and by the room within each vendor facility (referred to as "barrier") 19 and these differences can impact experimental output [20][21][22] .…”

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confidence: 86%

“…We previously reported a strong association between ter and Kp infection (pneumonia and bacteremia) in colonized patients, yet also found that terC is dispensable in a murine model of pneumonia 1 . To determine if ter is important for bloodstream infection, WT Kp and terC were competed in a peritoneal injection model of murine bacteremia.…”

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confidence: 89%

A plasmid locus associated withKlebsiellaclinical infections encodes a microbiome-dependent gut fitness factor

Vornhagen

Bassis

Ramakrishnan

et al. 2020

Preprint

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Introductory paragraphGut colonization by the pathogen Klebsiella pneumoniae (Kp) is consistently associated with subsequent Kp disease 1-5 , and patients are predominantly infected with their colonizing strain 1,2 . However, colonizing strains likely vary in their potential to cause infection. We previously identified the plasmid-encoded tellurium resistance (ter) operon as highly associated with infection when compared to asymptomatic colonization in hospitalized patients 1 . The ter operon bestows resistance to the toxic compound tellurite oxide (TeO3 -2 ), but this is unlikely to be its physiological function, as tellurium and TeO3 -2 are exceedingly rare. Here we show that terC is necessary and terZABCDEF is sufficient for phenotypic TeO3 -2 resistance. Next, we demonstrate that ter is encoded on a diverse group of plasmids without known plasmid-encoded virulence genes, suggesting an independent role in infection. Finally, our studies indicate that ter is a gut fitness factor, and its fitness advantage is conferred only when specific gut microbiota constituents are present. Collectively, these data reveal the Kp ter operon that is highly associated with human infection likely acts early in pathogenesis as a horizontally-transferrable fitness factor promoting robust gut colonization in the presence of the indigenous microbiota.3

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“…In recent years, the importance of this opportunistic pathogen has increased significantly due to an increase in virulence and resistance to antibiotic therapy [ 3 , 4 ]. K. pneumoniae strains were found to be heterogeneous in terms of virulence factors, and recent studies showed that some virulence factors are important for growth at specific tissue sites (lungs, urinary tract, liver, and blood) [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The New Klebsiella pneumoniae ST152 Variants with Hypermucoviscous Phenotype Isolated from Renal Transplant Recipients with Asymptomatic Bacteriuria—Genetic Characteristics by WGS

Wysocka

Zamudio

Oggioni

et al. 2020

Genes

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Klebsiella pneumoniae (Kp) is one of the most important etiological factors of urinary tract infections in renal transplant (RTx) recipients. We described the antimicrobial susceptibility phenotypes and genomic features of two hypermucoviscous (HM) Kp isolates recovered from RTx recipients with asymptomatic bacteriuria (ABU). Using whole genome sequencing (WGS) data, we showed that the strains belong to the ST152 lineage with the KL149 capsular serotype, but without rmpA/magA genes, which is typical for HM+ hypervirulent Kp. These new strains carried virulence-associated genes that predispose for urinary tract infections (UTIs). Likewise, both strains carried the ecp gene encoding pilus common for extended-spectrum β-lactamase (ESBL) Escherichia coli. Although the two ST152 isolates were closely related and differed by only nine single nucleotide polymorphisms (SNPs) in their chromosomes, they had different plasmid compositions and chromosomal elements, with isolate KP28872 carrying an ESBL plasmid and an integrative conjugative element. These two isolates are an example of the high plasticity of the K. pneumoniae accessory genome. The identification of patients with ABU matched with the correct epidemiological profiling of isolates could facilitate interventions to prevent or rapidly treat K. pneumoniae infections.

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Identification of Pathogenicity-Associated Loci in Klebsiella pneumoniae from Hospitalized Patients

Cited by 49 publications

References 47 publications

The Small Protein RmpD Drives Hypermucoviscosity in Klebsiella pneumoniae

The Small Protein RmpD Drives Hypermucoviscosity in Klebsiella pneumoniae

A plasmid locus associated withKlebsiellaclinical infections encodes a microbiome-dependent gut fitness factor

The New Klebsiella pneumoniae ST152 Variants with Hypermucoviscous Phenotype Isolated from Renal Transplant Recipients with Asymptomatic Bacteriuria—Genetic Characteristics by WGS

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