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

Mu, Andre; Klare, William P.; Baines, Sarah L.; Pang, Chi Nam Ignatius; Guérillot, Romain; Harbison-Price, Nichaela; Keller, Nadia; Wilksch, Jonathan J.; Nhu, Nguyen Thi Khanh; Phan, Minh-Duy; Keller, Bernhard; Nijagal, Brunda; Tull, Dedreia; Dayalan, Saravanan; Chua, Hwa Huat Charlie; Skoneczny, Dominik; Koval, Jason C.; Hachani, Abderrahman; Shah, Anup; Neha, Nitika; Jadhav, Snehal; Partridge, Sally R.; Cork, Amanda J.; Peters, Kate M.; Bertolla, Olivia M; Brouwer, Stephan; Hancock, Steven J.; Álvarez-Fraga, Laura; Oliveira, David M. P. De; Forde, Brian M.; Dale, Ashleigh; Mujchariyakul, Warasinee; Walsh, Calum J.; Monk, Ian R.; Fitzgerald, Anna; Lum, Mabel; Correa-Ospina, Carolina; Chowdhury, Piklu Roy; Parton, Robert G.; Voss, James J. De; Beckett, J. C.; Monty, Francois; McKinnon, Jessica; Song, Xiaomin; Stephen, J.; Everest, Marie; Bellgard, M.; Tinning, Matthew; Leeming, Michael G.; Hocking, Dianna M; Jebeli, Leila; Wang, Nancy; Zakour, Nouri L. Ben; Yasar, Serhat A.; Vecchiarelli, Stefano; Russell, Tonia; Zaw, Thiri; Chen, Tyrone; Teng, Don; Kassir, Zena; Lithgow, Trevor; Jenney, Adam; Cole, Jason N.; Nizet, Victor; Sorrell, Tania C.; Peleg, Anton Y.; Paterson, David L.; Beatson, Scott A.; Wu, Jemma X.; Molloy, Mark P.; Syme, Anna; Goode, Robert J. A.; Hunter, Adam; Bowland, Grahame; West, Nicholas P.; Wilkins, Marc R.; Djordjevic, Steven P.; Davies, Mark R.; Seemann, Torsten; Howden, Benjamin P; Pascovici, Dana; Tyagi, Sonika; Schittenhelm, Ralf B.; Souza, David P. De; McConville, Malcolm J.; Iredell, Jonathan R.; Cordwell, Stuart J.; Strugnell, Richard A.; Stinear, Timothy P.; Schembri, Mark A.; Walker, Mark J.

doi:10.1038/s41467-023-37200-w

Cited by 23 publications

(15 citation statements)

References 85 publications

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“…Predominant Gram-negative bacteria like E. coli, P. aeruginosa , and K. pneumonia harboring diverse resistance mechanisms have been previously identified as common sepsis-causing pathogens (Bloomfield et al, 2023; Mu et al, 2023). Some of these species have been linked to gut-to-lung bacterial migration and AMR acquisition and the worsening of sepsis (Wheatley et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Tracheal aspirate metagenomics reveals association of antibiotic resistance with non-pulmonary sepsis mortality

Rodríguez-Pérez,

Ciuffreda,

Hernández-Beeftink

et al. 2024

Preprint

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Background. Previous metabarcoding studies based on 16S rRNA sequencing in patients with extrapulmonary sepsis have found early pulmonary dysbiosis associated with a poor prognosis. To further discern this association, here we aimed to better characterize the pulmonary bacterial communities in these patients by leveraging metagenomics and to evaluate if the presence of antibiotic resistance genes (ARGs) could explain the higher mortality of the patients. Material and methods. Metagenomic sequencing was performed using the Nextera XT Library Prep Kit and HiSeq 4000 (Illumina Inc.) on tracheal aspirate samples that were obtained within 24 h from diagnosis from patients with extrapulmonary sepsis admitted to the Intensive Care Unit (ICU). Analysis involved MetaSpades for contig assembly, Kraken2 and Metaphlan4 for taxonomic classification, and CARD and GTDB-tk for ARGs annotation and assignment to the bacterial species. The relationship between the presence of antibiotic resistance and ICU mortality was evaluated using the Wilcoxon test and logistic regression models adjusting for clinical and demographic variables. Results. In total, 127 different ARGs were detected circumscribed only to seven patients. The most common ARGs found were from the antibiotic groups of aminoglycosides and beta-lactams, both present in most of the patients. These ARGs were found, almost entirely linked to Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The results also show a significant enrichment of ARGs among patients who died while admitted in the ICU (57%, 95% confidence interval [CI]: 18-90%) compared to surviving patients (20%, 95% CI: 7-40%) (p=0.022). Analyses adjusting for clinical and demographic variables did not alter this result. Conclusion. Metagenomic sequencing has allowed an unprecedented characterization of the sepsis lung microbiome showing that antibiotic resistance is common among these patients. The results also suggest a relationship between the early accumulation of ARGs in the lung of patients with extrapulmonary sepsis who die while admitted in the ICU. Studies in independent samples will be needed to validate our findings.

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Section: Discussionmentioning

confidence: 99%

Tracheal aspirate metagenomics reveals association of antibiotic resistance with non-pulmonary sepsis mortality

Rodríguez-Pérez,

Ciuffreda,

Hernández-Beeftink

et al. 2024

Preprint

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“…This could indicate an important role of regulation of VAGs but also of core genome genes in pathogenicity [ 76 ]. Differences in gene (VAG, metabolic gene) regulation between anatomical sites have been reported in Campylobacter coli [ 77 ], Klebsiella , Staphylococcus aureus and Streptococcus pyogenes [ 78 ]. Also, differences between E .…”

Section: Discussionmentioning

confidence: 99%

The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans

et al. 2023

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Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostic, prevention and treatment is still lacking. We used a collection of 912 BSI and 370 commensal E. coli isolates collected in France over a 17-year period (2000–2017). We compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity continuously increased through 1980, 2000, to 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.

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“…This distinction may have a huge impact on critical cellular attributes that control pathogenesis and resistance to antibiotics. 126 …”

Section: The Dynamic Relationship Between Lipid Chemical Structure Li...mentioning

confidence: 99%

The intricate link between membrane lipid structure and composition and membrane structural properties in bacterial membranes

Lee,

Charchar,

Separovic

et al. 2024

Chem. Sci.

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

Cited by 23 publications

References 85 publications

Tracheal aspirate metagenomics reveals association of antibiotic resistance with non-pulmonary sepsis mortality

Tracheal aspirate metagenomics reveals association of antibiotic resistance with non-pulmonary sepsis mortality

The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans

The intricate link between membrane lipid structure and composition and membrane structural properties in bacterial membranes

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