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RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence

Author

Listed:
  • Kejing Wu

    (Chinese Academy of Sciences)

  • Xingyu Lin

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yujie Lu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Rui Dong

    (Chinese Academy of Sciences)

  • Hongnian Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Sarah L. Svensson

    (Chinese Academy of Sciences)

  • Jiajia Zheng

    (Peking University Third Hospital)

  • Ning Shen

    (Peking University Third Hospital)

  • Andrew Camilli

    (Tufts University School of Medicine)

  • Yanjie Chao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

Abstract

Hypervirulent Klebsiella pneumoniae (HvKP) is an emerging bacterial pathogen causing invasive infection in immune-competent humans. The hypervirulence is strongly linked to the overproduction of hypermucoviscous capsule, but the underlying regulatory mechanisms of hypermucoviscosity (HMV) have been elusive, especially at the post-transcriptional level mediated by small noncoding RNAs (sRNAs). Using a recently developed RNA interactome profiling approach iRIL-seq, we interrogate the Hfq-associated sRNA regulatory network and establish an intracellular RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNAs that repress or promote HMV. One of the strongest HMV repressors is ArcZ, which is activated by the catabolite regulator CRP and targets many HMV-related genes including mlaA and fbp. We discover that MlaA and its function in phospholipid transport is crucial for capsule retention and HMV, inactivation of which abolishes Klebsiella virulence in mice. ArcZ overexpression drastically reduces bacterial burden in mice and reduces HMV in multiple hypervirulent and carbapenem-resistant clinical isolates, indicating ArcZ is a potent RNA inhibitor of bacterial pneumonia with therapeutic potential. Our work unravels a novel CRP-ArcZ-MlaA regulatory circuit of HMV and provides mechanistic insights into the posttranscriptional virulence control in a superbug of global concern.

Suggested Citation

  • Kejing Wu & Xingyu Lin & Yujie Lu & Rui Dong & Hongnian Jiang & Sarah L. Svensson & Jiajia Zheng & Ning Shen & Andrew Camilli & Yanjie Chao, 2024. "RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51213-z
    DOI: 10.1038/s41467-024-51213-z
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    References listed on IDEAS

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    1. Alexander J. Westermann & Konrad U. Förstner & Fabian Amman & Lars Barquist & Yanjie Chao & Leon N. Schulte & Lydia Müller & Richard Reinhardt & Peter F. Stadler & Jörg Vogel, 2016. "Dual RNA-seq unveils noncoding RNA functions in host–pathogen interactions," Nature, Nature, vol. 529(7587), pages 496-501, January.
    2. Jiang Yeow & Min Luo & Shu-Sin Chng, 2023. "Molecular mechanism of phospholipid transport at the bacterial outer membrane interface," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Michaela Huber & Anne Lippegaus & Sahar Melamed & Malte Siemers & Benjamin R. Wucher & Mona Hoyos & Carey Nadell & Gisela Storz & Kai Papenfort, 2022. "An RNA sponge controls quorum sensing dynamics and biofilm formation in Vibrio cholerae," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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