Xu Yidan, Guo Ruolan, Wang Ruomei, Su Zhe, Wu Yulu, Xie Chengbin, Wang Pinjia
School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan, China.
Department of Laboratory Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, Sichuan, China.
Virulence. 2025 Dec;16(1):2536186. doi: 10.1080/21505594.2025.2536186. Epub 2025 Jul 28.
Hypervirulent (hvKP), a pathogen responsible for severe invasive infections, exhibits a hypermucoviscosity (HMV) phenotype that is closely associated with its virulence. While fumarate and nitrate reduction regulator (FNR), a global transcription regulator, is critical for bacterial adaptation to hypoxic conditions, its role in hvKP pathogenicity remains unexplored. This study demonstrates that FNR modulates the HMV phenotype and virulence of the hvKP strain NTUH-K2044 under anaerobic conditions. Through targeted deletion and complementation of the gene, combined with phenotypic, molecular, cellular, and animal infection assays, we show that FNR positively regulates the HMV phenotype. Notably, this regulation is independent of several genes previously implicated in HMV formation, including , , (), , and . In the absence of , the HMV phenotype was abolished, while the transcript levels of these genes increased significantly, suggesting a compensatory or indirect regulatory mechanism that warrants further investigation. Functionally, FNR-mediated HMV enhanced bacterial resistance to phagocytosis and serum killing while suppressing host colonization features such as fimbriae formation, biofilm production, and epithelial cell adhesion. In animal infection models, FNR also contributed positively to hvKP virulence. These findings highlight the role of FNR in regulating the HMV phenotype and virulence in hvKP, facilitating host adaptation and immune evasion. Targeting FNR may thus represent a promising strategy for the development of novel therapeutics.
高毒力肺炎克雷伯菌（hvKP）是一种引起严重侵袭性感染的病原体，表现出与毒力密切相关的高黏液黏稠度（HMV）表型。虽然全局转录调节因子富马酸盐和硝酸盐还原调节因子（FNR）对细菌适应低氧条件至关重要，但其在hvKP致病性中的作用仍未得到探索。本研究表明，FNR在厌氧条件下调节hvKP菌株NTUH-K2044的HMV表型和毒力。通过对该基因进行靶向缺失和互补，结合表型、分子、细胞和动物感染试验，我们发现FNR正向调节HMV表型。值得注意的是，这种调节独立于先前涉及HMV形成的几个基因，包括、、（）、和。在缺乏时，HMV表型消失，而这些基因的转录水平显著增加，提示存在一种值得进一步研究的补偿性或间接调节机制。在功能上，FNR介导的HMV增强了细菌对吞噬作用和血清杀伤的抗性，同时抑制了如菌毛形成、生物膜产生和上皮细胞黏附等宿主定植特征。在动物感染模型中，FNR对hvKP毒力也有正向作用。这些发现突出了FNR在调节hvKP的HMV表型和毒力、促进宿主适应和免疫逃逸中的作用。因此，靶向FNR可能是开发新型治疗方法的一个有前景的策略。
