MrkA enhances the virulence phenotype of carbapenem-resistant Klebsiella pneumoniae both in vitro and in vivo

 Highlights

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    MrkA is required for siderophore production, revealing an unexpected link between type 3 fimbriae and iron acquisition.
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    MrkA could mediates bacterial adhesion to bladder and intestinal epithelium, indicating a role in mucosal tropism.
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    MrkA maintains carbon homeostasis via the PTS and csrA, and its loss reprograms metabolism and attenuates virulence.

Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a severe threat to public health, but the factors underlying its virulence are not fully understood. This study identified a novel and critical role for the type 3 fimbrial component MrkA in orchestrating CRKP pathogenesis through mechanisms extending far beyond its canonical function in adhesion. We demonstrated that mrkA deletion in a clinical CRKP strain severely impairs siderophore production, uncovering an unexpected link between fimbrial function and iron uptake. Furthermore, the mutant exhibited a specific defect in its capacity to adhere to both bladder and intestinal epithelial cells, suggesting a previously unrecognized role for mrkA in mediating the tropism to key mucosal sites preceding invasion. Transcriptomic analysis revealed that mrkA is essential for maintaining bacterial carbon homeostasis, as its suppression led to a profound dysregulation of carbohydrate transport systems, including the phosphotransferase system (PTS) and ABC transporters, as well as the global regulator csrA. This metabolic reprogramming was accompanied by a noticeable decrease in the virulence of the strain in a murine model, with tissue damage and pro-inflammatory cytokine response (IL-1β, IL-6) being ameliorated in comparison to a wild-type strain. Our findings redefine mrkA as a central regulator that integrates nutritional competence (iron and carbon uptake) with epithelial adhesion to drive systemic CRKP infection.

Read full article for free (open access):
https://www.sciencedirect.com/science/article/pii/S2666517426000398



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