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RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence
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RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence
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Journal Article
RNA interactome of hypervirulent Klebsiella pneumoniae reveals a small RNA inhibitor of capsular mucoviscosity and virulence
2024
Overview
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.
By performing a global RNA-RNA interactome analysis in hypervirulent
Klebsiella pneumoniae
, the authors identify the small RNA ArcZ targets many capsule genes and a key virulence factor MlaA, inhibiting
Klebsiella
infection and pathogenesis in mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 49/90
/ 49/91
/ 64/60
/ Animals
/ Bacteria
/ Bacterial Capsules - genetics
/ Bacterial Capsules - metabolism
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Female
/ Gene Expression Regulation, Bacterial
/ Genes
/ Host Factor 1 Protein - genetics
/ Host Factor 1 Protein - metabolism
/ Humanities and Social Sciences
/ Humans
/ Klebsiella Infections - microbiology
/ Klebsiella pneumoniae - genetics
/ Klebsiella pneumoniae - metabolism
/ Klebsiella pneumoniae - pathogenicity
/ Mice
/ Regulatory mechanisms (biology)
/ RNA
/ RNA, Small Untranslated - genetics
/ RNA, Small Untranslated - metabolism
/ Science
