RIL-seq reveals extensive involvement of small RNAs in virulence and capsule regulation in hypervirulent Klebsiella pneumoniae

Author:

Goh Kwok Jian123,Altuvia Yael4,Argaman Liron4,Raz Yair4,Bar Amir4,Lithgow Trevor3ORCID,Margalit Hanah4ORCID,Gan Yunn-Hwen12ORCID

Affiliation:

1. Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore  117545 , Singapore

2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Singapore  117596 , Singapore

3. Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University , Clayton , Victoria , Australia

4. Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 9112102, Israel

Abstract

Abstract Hypervirulent Klebsiella pneumoniae (hvKp) can infect healthy individuals, in contrast to classical strains that commonly cause nosocomial infections. The recent convergence of hypervirulence with carbapenem-resistance in K. pneumoniae can potentially create ‘superbugs’ that are challenging to treat. Understanding virulence regulation of hvKp is thus critical. Accumulating evidence suggest that posttranscriptional regulation by small RNAs (sRNAs) plays a role in bacterial virulence, but it has hardly been studied in K. pneumoniae. We applied RIL-seq to a prototypical clinical isolate of hvKp to unravel the Hfq-dependent RNA-RNA interaction (RRI) network. The RRI network is dominated by sRNAs, including predicted novel sRNAs, three of which we validated experimentally. We constructed a stringent subnetwork composed of RRIs that involve at least one hvKp virulence-associated gene and identified the capsule gene loci as a hub target where multiple sRNAs interact. We found that the sRNA OmrB suppressed both capsule production and hypermucoviscosity when overexpressed. Furthermore, OmrB base-pairs within kvrA coding region and partially suppresses translation of the capsule regulator KvrA. This agrees with current understanding of capsule as a major virulence and fitness factor. It emphasizes the intricate regulatory control of bacterial phenotypes by sRNAs, particularly of genes critical to bacterial physiology and virulence.

Funder

NRF-ISF Israel-Singapore Binational

ERC

NHMRC

Publisher

Oxford University Press (OUP)

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