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Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

ABSTRACT: Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

SUBMITTER: Mu A

PROVIDER: S-EPMC10024524 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

Mu Andre A Klare William P WP Baines Sarah L SL Ignatius Pang C N CN Guérillot Romain R Harbison-Price Nichaela N Keller Nadia N Wilksch Jonathan J Nhu Nguyen Thi Khanh NTK Phan Minh-Duy MD Keller Bernhard B Nijagal Brunda B Tull Dedreia D Dayalan Saravanan S Chua Hwa Huat Charlie HHC Skoneczny Dominik D Koval Jason J Hachani Abderrahman A Shah Anup D AD Neha Nitika N Jadhav Snehal S Partridge Sally R SR Cork Amanda J AJ Peters Kate K Bertolla Olivia O Brouwer Stephan S Hancock Steven J SJ Álvarez-Fraga Laura L De Oliveira David M P DMP Forde Brian B Dale Ashleigh A Mujchariyakul Warasinee W Walsh Calum J CJ Monk Ian I Fitzgerald Anna A Lum Mabel M Correa-Ospina Carolina C Roy Chowdhury Piklu P Parton Robert G RG De Voss James J Beckett James J Monty Francois F McKinnon Jessica J Song Xiaomin X Stephen John R JR Everest Marie M Bellgard Matt I MI Tinning Matthew M Leeming Michael M Hocking Dianna D Jebeli Leila L Wang Nancy N Ben Zakour Nouri N Yasar Serhat A SA Vecchiarelli Stefano S Russell Tonia T Zaw Thiri T Chen Tyrone T Teng Don D Kassir Zena Z Lithgow Trevor T Jenney Adam A Cole Jason N JN Nizet Victor V Sorrell Tania C TC Peleg Anton Y AY Paterson David L DL Beatson Scott A SA Wu Jemma J Molloy Mark P MP Syme Anna E AE Goode Robert J A RJA Hunter Adam A AA Bowland Grahame G West Nicholas P NP Wilkins Marc R MR Djordjevic Steven P SP Davies Mark R MR Seemann Torsten T Howden Benjamin P BP Pascovici Dana D Tyagi Sonika S Schittenhelm Ralf B RB De Souza David P DP McConville Malcolm J MJ Iredell Jonathan R JR Cordwell Stuart J SJ Strugnell Richard A RA Stinear Timothy P TP Schembri Mark A MA Walker Mark J MJ

Nature communications 20230318 1

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, ...[more]

PMID: 36934086

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Project description:Bacteria constantly face stress conditions and therefore mount specific responses to ensure adaptation and survival. Stress responses were believed to be predominantly regulated at the transcriptional level. In the phototrophic bacterium Rhodobacter sphaeroides the response to singlet oxygen is initiated by alternative sigma factors. Further adaptive mechanisms include post-transcriptional and post-translational events, which have to be considered to gain a deeper understanding of how sophisticated regulation networks operate. To address this issue, we integrated three layers of regulation: (1) total mRNA levels at different time-points revealed dynamics of the transcriptome, (2) mRNAs in polysome fractions reported on translational regulation (translatome), and (3) SILAC-based mass spectrometry was used to quantify protein abundances (proteome). The singlet oxygen stress response exhibited highly dynamic features regarding short-term effects and late adaptation, which could in part be assigned to the sigma factors RpoE and RpoH2 generating distinct expression kinetics of corresponding regulons. The occurrence of polar expression patterns of genes within stress-inducible operons pointed to an alternative of dynamic fine-tuning upon stress. In addition to transcriptional activation, we observed significant induction of genes at the post-transcriptional level (translatome), which identified new putative regulators and assigned genes of quorum sensing to the singlet oxygen stress response. Intriguingly, the SILAC approach explored the stress-dependent decline of photosynthetic proteins, but also identified 19 new open reading frames, which were partly validated by RNA-seq. We propose that comparative approaches as presented here will help to create multi-layered expression maps on the system level ("expressome"). Finally, intense mass spectrometry combined with RNA-seq might be the future tool of choice to re-annotate genomes in various organisms and will help to understand how they adapt to alternating conditions.

Dataset Information

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

Publications

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

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