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The hypermucoviscosity of hypervirulent K. pneumoniae confers the ability to evade neutrophil-mediated phagocytosis.

ABSTRACT: Hypervirulent Klebsiella pneumoniae (HvKP), which causes highly fatal infections, is a new threat to human health. In an attempt to investigate the underlying mechanisms of resistance to neutrophil-mediated killing and hence expression of high-level virulence by HvKP, we tested the binding affinity of HvKP strains to various types of human cells. Our data showed that HvKP exhibited weaker binding to both lung epithelial cells, intestinal Caco-2 cells and macrophages when compared to the classic, non-hypervirulent strains (cKP). Consistently, transconjugants that have acquired a rmpA or rmpA2-bearing plasmid were found to exhibit decreased adhesion to various types of human cells, and hence higher survival rate upon exposure to neutrophil cells. We further found that over production of hypermucoviscosity (HMV), but not capsular polysaccharide (CPS), contributed to the reduced binding and phagocytosis. The effect of hypermucoviscosity on enhancing HvKP virulence was further shown in human serum survival assays and animal experiments. Findings in this study therefore confirmed that rmpA/A2-mediated hypermucoviscosity in HvKP plays a key role in the pathogenesis of this organism through conferring the ability to evade neutrophil binding and phagocytosis.

SUBMITTER: Xu Q

PROVIDER: S-EPMC8331041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The polysaccharide capsule is an essential virulence factor for Klebsiella pneumoniae in both community-acquired hypervirulent strains as well as health care-associated classical strains that are posing significant challenges due to multidrug resistance. Capsule production is known to be transcriptionally regulated by a number of proteins, but very little is known about how these proteins collectively control capsule production. RmpA and RcsB are two known regulators of capsule gene expression, and RmpA is required for the hypermucoviscous (HMV) phenotype in hypervirulent K. pneumoniae strains. In this report, we confirmed that these regulators performed their anticipated functions in the ATCC 43816 derivative, KPPR1S: rcsB and rmpA mutants are HMV negative and have reduced capsule gene expression. We also identified a novel transcriptional regulator, RmpC, encoded by a gene near rmpA The ΔrmpC strain has reduced capsule gene expression but retains the HMV phenotype. We further showed that a regulatory cascade exists in which KvrA and KvrB, the recently characterized MarR-like regulators, and RcsB contribute to capsule regulation through regulation of the rmpA promoter and through additional mechanisms. In a murine pneumonia model, the regulator mutants have a range of colonization defects, suggesting that they regulate virulence factors in addition to capsule. Further testing of the rmpC and rmpA mutants revealed that they have distinct and overlapping functions and provide evidence that HMV is not dependent on overproduction of capsule. This distinction will facilitate a better understanding of HMV and how it contributes to enhanced virulence of hypervirulent strains.IMPORTANCE Klebsiella pneumoniae continues to be a substantial public health threat due to its ability to cause health care-associated and community-acquired infections combined with its ability to acquire antibiotic resistance. Novel therapeutics are needed to combat this pathogen, and a greater understanding of its virulence factors is required for the development of new drugs. A key virulence factor for K. pneumoniae is the capsule, and community-acquired hypervirulent strains produce a capsule that causes hypermucoidy. We report here a novel capsule regulator, RmpC, and provide evidence that capsule production and the hypermucoviscosity phenotype are distinct processes. Infection studies showing that this and other capsule regulator mutants have a range of phenotypes indicate that additional virulence factors are in their regulons. These results shed new light on the mechanisms controlling capsule production and introduce targets that may prove useful for the development of novel therapeutics for the treatment of this increasingly problematic pathogen.

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The hypermucoviscosity of hypervirulent K. pneumoniae confers the ability to evade neutrophil-mediated phagocytosis.

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