Two-Component Response Regulator OmpR Regulates Mucoviscosity through Energy Metabolism in Klebsiella pneumoniae.

Autor:	Wang L; Center for Infectious Disease Research, Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China.; Department of Laboratory Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China., Huang X; Center for Infectious Disease Research, Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China., Jin Q; Center for Infectious Disease Research, Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China., Tang J; Department of Laboratory Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China., Zhang H; Department of Integrative Biomedical and Diagnostic Sciences, Oregon Health and Science University School of Dentistry, Portland, Oregon, USA., Zhang JR; Center for Infectious Disease Research, Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China.; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China., Wu H; Department of Integrative Biomedical and Diagnostic Sciences, Oregon Health and Science University School of Dentistry, Portland, Oregon, USA.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2023 Jun 15; Vol. 11 (3), pp. e0054423. Date of Electronic Publication: 2023 Apr 25.
DOI:	10.1128/spectrum.00544-23
Abstrakt:	Hypermucoviscosity is a hallmark of hypervirulent Klebsiella pneumoniae (hvKP). However, the molecular basis of its regulation is largely unknown. We hypothesize that hypermucoviscosity is modulated via two-component signal transduction systems (TCSs). In-frame deletion mutants of all 33 response regulators of hvKP ATCC43816 were generated using CRISPR/CAS and evaluated for their impacts on hypermucoviscosity. The response regulator OmpR is required for hypermucoviscosity in vitro and virulence in vivo in a mouse pneumonia model. The Δ ompR mutant lost its mucoidy but retained its capsule level and comparable rmpADC expression, so transcriptomic analysis by RNA-Seq was performed to identify differentially expressed genes (DEGs) in Δ ompR mutant. The top 20 Gene Ontology terms of 273 DEGs belong to purine ribonucleotide triphosphate biosynthetic and metabolic process, transmembrane transport, and amino acid metabolism. Among the overexpressed genes in the Δ ompR mutant, the atp operon encoding F-type ATP synthase and the gcvTHP encoding glycine cleavage system were characterized further as overexpression of either operon reduced the mucoviscosity and increased the production of ATP. Furthermore, OmpR directly bound the promoter region of the atp operon, not the gcvTHP , suggesting that OmpR regulates the expression of the atp operon directly and gcvTHP indirectly. Hence, the loss of OmpR led to the overexpression of F-type ATP synthase and glycine cleavage system, which altered the energetic status of Δ ompR cells and contributed to the subsequent reduction in the mucoviscosity. Our study has uncovered a previously unknown regulation of bacterial metabolism by OmpR and its influence on hypermucoviscosity. IMPORTANCE Hypermucoviscosity is a critical virulent factor for Klebsiella pneumoniae infections, and its regulation remains poorly understood at the molecular level. This study aims to address this knowledge gap by investigating the role of response regulators in mediating hypermucoviscosity in K. pneumoniae. We screened 33 response regulators and found that OmpR is essential for hypermucoviscosity and virulence of K. pneumoniae in a mouse pneumonia model. Transcriptomic analysis uncovered that genes involved in energy production and metabolism are highly upregulated in the Δ ompR mutant, suggesting a potential link between bacterial energy status and hypermucoviscosity. Overexpression of those genes increased production of ATP and reduced mucoviscosity, recapitulating the Δ ompR mutant phenotype. Our findings provide new insights into the regulation of K. pneumoniae hypermucoviscosity by a two-component signal transduction system, highlighting the previously unknown role of OmpR in regulating bacterial energy status and its influence on hypermucoviscosity. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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