Next-generation sequencing based hospital outbreak investigation yields insight into Klebsiella aerogenes population structure and determinants of carbapenem resistance and virulence

Malek, A.; McGlynn, K.; Taffner, S.; Fine, L.; Tesini, B.; Wang, J.; Mostafa, H. H.; Petry, S.; Perkins, A.; Graman, P.; Hardy, D. J.; Pecora, N. D.

doi:10.1101/497958

bioRxiv · 10.1101/497958

Next-generation sequencing based hospital outbreak investigation yields insight into Klebsiella aerogenes population structure and determinants of carbapenem resistance and virulence

Malek, A.·McGlynn, K.·Taffner, S.·Fine, L.·Tesini, B.·Wang, J.·Mostafa, H. H.·Petry, S.·Perkins, A.·Graman, P.·Hardy, D. J.·Pecora, N. D.

View original source ↗Export metadata ↓

Abstract

Klebsiella aerogenes is a nosocomial pathogen associated with drug resistance and outbreaks in intensive care units. In a 5-month period in 2017, we experienced an increased incidence of cultures for carbapenem-resistant K. aerogenes (CR-KA) from an adult cardiothoracic intensive care unit (CICU) involving 15 patients. Phylogenomic analysis following whole-genome sequencing (WGS) identified the outbreak CR-KA isolates to group together as a tight clonal cluster (<7 SNPs apart), suggestive of a protracted intra-ward transmission event. No clonal relationships were identified between the CICU CR-KA strains and additional hospital CR-KA patient isolates from different wards and/or previous years. Genes encoding carbapenemases or drug-resistant plasmids were absent in the outbreak strains, and carbapenem resistance was attributed to mutations impacting AmpD activity and membrane permeability. The CICU outbreak strains harbored an integrative conjugative element (ICEKp10), which has been associated with pathogenicity in hypervirulent Klebsiella pneumoniae lineages. Comparative genomics with global K. aerogenes genomes showed our outbreak strains to group closely with global ST4 strains, which along with ST93 likely represent dominant K. aerogenes lineages associated with human infections. WGS is a powerful tool that goes beyond high-resolution tracking of transmission events into identifying the genetic basis of drug-resistance and virulence, which are not part of conventional diagnostic workflows. With an increasing availability of sequenced genomes from across the globe, population structure analysis offers opportunities to identify emerging trends and dominant clones associated with specific syndromes and geographical locations for poorly characterized pathogens.

Source connections

Published article ↗

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Malek, A., McGlynn, K., Taffner, S., Fine, L., Tesini, B., Wang, J., Mostafa, H. H., Petry, S., Perkins, A., Graman, P., Hardy, D. J., Pecora, N. D.. 2018-12-17. Next-generation sequencing based hospital outbreak investigation yields insight into Klebsiella aerogenes population structure and determinants of carbapenem resistance and virulence. https://doi.org/10.1101/497958

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

SPACE-Tag Enables High-Throughput Spatial Chromatin Profiling With CUT&Tag

Spatial epigenomics maps chromatin states within intact tissues, yet current methods remain limited by accessibility and scale. We developed SPACE-Tag, a spatial CUT&Tag framework that converts epigenetic marks-associated DNA into polyadenylated RNA through T7 based linear amplification, enabling direct integration with standard spatial transcriptomic workflows. Applied to the mouse brain, SPACETag resolved activating and repressive chromatin landscapes, recovered region-specific gene regulatory programs across anatomical domains, and showed strong correlation with existing bulk and single cell reference data. We generated an integrated multimodal atlas of the aging mouse brain, profiling five histone modifications and the transcriptome in parallel across the adult lifespan to establish the largest spatial multimodal dataset to date. This analysis uncovered sharp regional divergence with aging in the brain: fiber tracts showed widespread transcriptional downregulation, often without nearby chromatin state transitions, whereas the isocortex showed coordinated chromatin transcriptome changes, including an H3K4me1 peak module that increased with age, was enriched at super-enhancers and linked to upregulation of neuronal plasticity regulators. These findings highlight the power of multimodal and high throughput spatial genomics in uncovering the divergent regulatory logic that governs tissue-specific vulnerability and resilience in the aging brain.

genomics↗

bioRxiv2026

Long-read DNA sequencing reveals global hypomethylation and focal hypermethylation in SDHx-deficient pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas (PPGL) are highly heritable neuroendocrine tumors of the autonomic ganglia. Genomic DNA in most cancer cells is hypomethylated. However, DNA in PPGLs secondary to mutations in succinate dehydrogenase complex (SDHx) genes is reportedly hypermethylated due to succinate-mediated inhibition of DNA demethylases. We used nanopore long-read sequencing to characterize the methylome of tumor and white blood cell DNA from SDHx and non-SDHx PPGL patients, alongside normal adrenal medulla. We find that both SDHx and non-SDHx PPGLs are globally hypomethylated, particularly at centromeres. In normal adrenal medulla, CpG islands marked by H3K4 methylation are hypomethylated, whereas CpG islands lacking H3K4 methylation are hypermethylated. In SDHx-related PPGL, some H3K4me-marked CpG islands are hypermethylated, but most are not. We propose that DNA methylation in SDHx-related PPGL reflects the global hypomethylation generally observed in tumors, partly offset by succinate-mediated inhibition of TET DNA demethylases. Opposing effects of succinate may alter the balance between DNA methylation (indirect inhibition of the DNMT3A/B DNA methylases via inhibition of H3K4me demethylases) and DNA demethylation (inhibition of TET DNA demethylases) at active CpG islands.

genomics↗

bioRxiv2026

High piRNA abundance is a hallmark of evolutionarily persistent piRNA-producing loci.

PIWI-interacting RNAs (piRNAs) silence transposons in the germline, and the loci that produce them diverge rapidly between species. Yet, some loci retain both their genomic location and their piRNA production across large evolutionary distances, and the basis for this conservation is unclear. To identify the features that distinguish these persistent loci, we compared piRNA production at orthologous loci in three closely related mouse species, contrasting loci that produce piRNAs in all three species with those that do so in only one. Transposon content and UTR features, often linked to piRNA production, did not distinguish the two groups. Transcription extending beyond gene ends (readthrough) was more frequent at conserved loci, but did not explain conservation once the amount of piRNAs produced was taken into account. Instead, we found that the conserved loci are those that produce the most piRNAs. The same association holds true in human and two other primate species. We speculate that most piRNAs expressed in testis are tolerated molecular noise, and that only the highly expressed minority are likely to be functional.

genomics↗