Scholarlink

<p>Infective endocarditis (IE) is a severe heart infection caused predominantly by Gram-positive bacteria forming biofilm on heart valves. While biofilm formation is central to disease progression, the underlying bacterial mechanisms remain poorly understood. Here, we identify the Fsr quorum sensing (QS) system of <i>Enterococcus faecalis</i> as an unexpected negative regulator of biofilm and pathogenesis in IE. Using microfluidic and in vivo models, we show that blood flow prevents Fsr activation in early IE, with Fsr induction occurring only later, once bacteria form biofilm microcolonies and become shielded from flow. Deletion of Fsr promotes robust biofilm growth, driven partly through the downregulation of GelE and SprE proteases, reprograms metabolism by upregulating <i>lrgAB</i> to enhance pyruvate utilization, and increases gentamicin tolerance in vivo. Furthermore, we show that GelE cleaves the human pro-IL-1β into an active form, suggesting a species-specific mechanism for inflammation modulation by QS. In support of these findings, analysis of IE patient cohorts shows that naturally occurring Fsr-deficient <i>E. faecalis</i> strains are associated with prolonged bacteremia. Overall, our findings provide insights into how host blood flow impacts QS activation, which, in turn, regulates pathogenesis in IE, and highlight the Fsr QS as a potential determinant of clinical disease course.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Loss of Fsr quorum sensing promotes biofilm formation and worsens outcomes in enterococcal infective endocarditis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月14日

查看全文
  • Haris Antypas,
  • Verena Schmidtchen,
  • Willy Isao Staiger,
  • LI Yanhong,
  • Rachel Jing Wen Tan,
  • Kenneth Kok Fei NG,
  • Cheryl Jia Yi Neo,
  • Shalome Meera Radhesh,
  • Frederick Reinhart Tanoto,
  • Ronni Anderson Gonçalves da Silva,
  • Cristina Colomer-Winter,
  • Sara Doina Schütz,
  • Joachim Kloehn,
  • Logeshwari Muthualagu Natarajan,
  • Caroline Manzano,
  • Jun Jie Wong,
  • Kevin Pethe,
  • Barbara Hasse,
  • Silvio Daniel Brugger,
  • Siu Ling Wong,
  • Daria Van Tyne,
  • Annelies S. Zinkernagel,
  • Kimberly A. Kline

摘要

Infective endocarditis (IE) is a severe heart infection caused predominantly by Gram-positive bacteria forming biofilm on heart valves. While biofilm formation is central to disease progression, the underlying bacterial mechanisms remain poorly understood. Here, we identify the Fsr quorum sensing (QS) system of Enterococcus faecalis as an unexpected negative regulator of biofilm and pathogenesis in IE. Using microfluidic and in vivo models, we show that blood flow prevents Fsr activation in early IE, with Fsr induction occurring only later, once bacteria form biofilm microcolonies and become shielded from flow. Deletion of Fsr promotes robust biofilm growth, driven partly through the downregulation of GelE and SprE proteases, reprograms metabolism by upregulating lrgAB to enhance pyruvate utilization, and increases gentamicin tolerance in vivo. Furthermore, we show that GelE cleaves the human pro-IL-1β into an active form, suggesting a species-specific mechanism for inflammation modulation by QS. In support of these findings, analysis of IE patient cohorts shows that naturally occurring Fsr-deficient E. faecalis strains are associated with prolonged bacteremia. Overall, our findings provide insights into how host blood flow impacts QS activation, which, in turn, regulates pathogenesis in IE, and highlight the Fsr QS as a potential determinant of clinical disease course.