# Succinate-driven virulence enhancement in hypervirulent Klebsiella pneumoniae via DcuSR two-component system

## TL;DR

This study shows how succinate boosts the virulence of hypervirulent Klebsiella pneumoniae in the gut through a specific signaling system.

## Contribution

The novel finding is that succinate activates virulence traits in hvKP via the DcuSR two-component system.

## Key findings

- Succinate activates type VI secretion system genes via the DcuSR TCS, increasing cytotoxicity.
- Succinate promotes adherence via type III fimbriae expression through the DcuSR TCS.
- Succinate serves as a metabolic substrate for ATP synthesis, aiding energy production in hvKP.

## Abstract

Hypervirulent Klebsiella pneumoniae (hvKP) primarily colonizes the mammalian gastrointestinal tract, and it is prone to causing invasive infections under specific conditions. To establish infection, hvKP must compete with the resident gut microbiota for essential nutrients. This study focuses on the C4-dicarboxylate (C4-DC) succinate, which has been reported to accumulate in the gut under specific pathological conditions. We demonstrate that hvKP utilizes succinate as a signaling molecule to enhance virulence gene expression. Specifically, extracellular succinate activates type VI secretion system gene expression via the DcuSR two-component system (TCS), thereby increasing cytotoxicity toward intestinal epithelial cells and enhancing competitiveness against commensal Escherichia coli. Additionally, succinate facilitates the expression of type III fimbriae via the DcuSR TCS, promoting hvKP adherence to intestinal epithelial cells. Beyond its signaling role, succinate functions as a metabolic substrate and contributes to adenosine 5′-triphosphate (ATP) synthesis, potentially through C4-dicarboxylic acid transporters DctA or DcuB to boost energy synthesis. This study focuses on elucidating the impact of succinate in regulating hvKP virulence, with particular attention to the potential role of the DcuSR TCS in hvKP pathogenesis.

Succinate, a C4-DC, is produced by the host and the gut microbiota and can accumulate in the intestinal environment under various pathological conditions, such as diabetes and inflammatory bowel disease. It acts as a pivotal regulator of virulence traits and metabolic pathways in Enterobacteriaceae. Our findings highlight the significant impact of succinate on hvKP pathogenesis: (i) functioning through the DcuSR TCS to activate virulence programs and (ii) serving as a metabolic substrate that fuels bioenergetic adaptation through ATP synthesis.