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

Kejing Wu, Xingyu Lin, Yujie Lu, Rui Dong, Hongnian Jiang, Sarah L. Svensson, Jiajia Zheng, Ning Shen, Andrew Camilli and Yanjie Chao ()
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Kejing Wu: Chinese Academy of Sciences
Xingyu Lin: Chinese Academy of Sciences
Yujie Lu: Chinese Academy of Sciences
Rui Dong: Chinese Academy of Sciences
Hongnian Jiang: 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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51213-z

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