ABSTRACT
BACKGROUND: Klebsiella pneumoniae is a major bacterial and opportunistic human pathogen, increasingly recognized as a healthcare burden globally. The convergence of resistance and virulence in K. pneumoniae strains has led to the formation of hypervirulent and multidrug-resistant strains with dual risk, limiting treatment options. K. pneumoniae clones are known to emerge locally and spread globally. Therefore, an understanding of the dynamics and evolution of the emerging strains in hospitals is warranted to prevent future outbreaks. METHODS: In this study, we conducted an in-depth genomic analysis on a large-scale collection of 328 multidrug-resistant (MDR) K. pneumoniae strains recovered from 239 patients from a single major hospital in the western coastal city of Jeddah in Saudi Arabia from 2014 through 2022. We employed a broad range of phylogenetic and phylodynamic methods to understand the evolution of the predominant clones on epidemiological time scales, virulence and resistance determinants, and their dynamics. We also integrated the genomic data with detailed electronic health record (EHR) data for the patients to understand the clinical implications of the resistance and virulence of different strains. RESULTS: We discovered a diverse population underlying the infections, with most strains belonging to Clonal Complex 14 (CC14) exhibiting dominance. Specifically, we observed the emergence and continuous expansion of strains belonging to the dominant ST2096 in the CC14 clade across hospital wards in recent years. These strains acquired resistance mutations against colistin and extended spectrum ß-lactamase (ESBL) and carbapenemase genes, namely blaOXA-48 and blaOXA-232, located on three distinct plasmids, on epidemiological time scales. Strains of ST2096 exhibited a high virulence level with the presence of the siderophore aerobactin (iuc) locus situated on the same mosaic plasmid as the ESBL gene. Integration of ST2096 with EHR data confirmed the significant link between colonization by ST2096 and the diagnosis of sepsis and elevated in-hospital mortality (p-value < 0.05). CONCLUSIONS: Overall, these results demonstrate the clinical significance of ST2096 clones and illustrate the rapid evolution of an emerging hypervirulent and MDR K. pneumoniae in a clinical setting.
Subject(s)
Klebsiella pneumoniae , Klebsiella , Humans , Klebsiella/genetics , Tertiary Care Centers , Phylogeny , Plasmids/genetics , beta-Lactamases/genetics , Anti-Bacterial AgentsABSTRACT
We model the evolutionary epidemiology of spore-producing plant pathogens in heterogeneous environments sown with several cultivars carrying quantitative resistances. The model explicitly tracks the infection-age structure and genetic composition of the pathogen population. Each strain is characterized by pathogenicity traits describing its infection efficiency and a time-varying sporulation curve taking into account lesion ageing. We first derive a general expression of the basic reproduction number [R]0 for fungal pathogens in heterogeneous environments. We show that evolutionary attractors of the model coincide with local maxima of [R]0 only if the infection efficiency is the same on all host types. We then study how three basic resistance characteristics (pathogenicity trait targeted, resistance effectiveness, and adaptation cost) in interaction with the deployment strategy (proportion of fields sown with a resistant cultivar) (i) lead to pathogen diversification at equilibrium and (ii) shape the transient dynamics from evolutionary and epidemiological perspectives. We show that quantitative resistance impacting only the sporulation curve will always lead to a monomorphic population, while dimorphism (i.e. pathogen diversification) can occur with resistance altering infection efficiency, notably with high adaptation cost and proportion of R cultivar. Accordingly, the choice of quantitative resistance genes operated by plant breeders is a driver of pathogen diversification. From an evolutionary perspective, the emergence time of the evolutionary attractor best adapted to the R cultivar tends to be shorter when the resistance impacts infection efficiency than when it impacts sporulation. In contrast, from an epidemiological perspective, the epidemiological control is always higher when the resistance impacts infection efficiency. This highlights the difficulty of defining deployment strategies of quantitative resistance maximising at the same time epidemiological and evolutionary outcomes.
ABSTRACT
Monitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. The availability of patient hospital records is crucial for linking the genomic sequence information to virus function during the course of infections. Here, we sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia from March to August 2020. From the assembled sequences, we estimate the SARS-CoV-2 effective population size and infection rate and outline the epidemiological dynamics of import and transmission events during this period in Saudi Arabia. We show that two consecutive mutations (R203K/G204R) in the SARS-CoV-2 nucleocapsid (N) protein are associated with higher viral loads in COVID-19 patients. Our comparative biochemical analysis reveals that the mutant N protein displays enhanced viral RNA binding and differential interaction with key host proteins. We found hyper-phosphorylation of the adjacent serine site (S206) in the mutant N protein by mass-spectrometry analysis. Furthermore, analysis of the host cell transcriptome suggests that the mutant N protein results in dysregulated interferon response genes. We provide crucial information in linking the R203K/G204R mutations in the N protein as a major modulator of host-virus interactions and increased viral load and underline the potential of the nucleocapsid protein as a drug target during infection.
