Abstract
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.
Highlights
Klebsiella pneumoniae has a remarkable ability to cause a wide range of human diseases
Previous studies established that loss of rmpA decreases capsule gene expression and reduces HMV in commonly used hypervirulent K. pneumoniae (hvKp) strains [31, 32]. We recently confirmed these rmpA-dependent phenotypes in the hvKp strain KPPR1S [28]. We described another regulator of capsule gene expression, RmpC, which is encoded downstream of rmpA; rmpA and rmpC are cotranscribed from the same promoter that is positively regulated by RmpA [28]
Hypermucoviscosity (HMV) is a phenotype possessed by a subset of K. pneumoniae strains and is one of the phenotypes associated with hypervirulent strains [2]
Summary
Klebsiella pneumoniae has a remarkable ability to cause a wide range of human diseases. 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). 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. There have been recent reports of extensively resistant hypervirulent K. pneumoniae [18, 19], and multiple strains where both hv-associated genes and antimicrobial resistance genes were present on the same mobile vector [20,21,22,23] These reports of convergence of hypervirulence and antimicrobial resistance in the same strain have heightened the need to better understand how hypervirulence genes interface with a strain’s genetic background to confer hypervirulent phenotypes. This is important given the extensive diversity of genetic content between K. pneumoniae strains
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