PhD defence Wim Cuypers

Supervisors

• Prof. dr. Kris Laukens (University of Antwerp)

• Prof. dr. Sandra Van Puyvelde (University of Antwerp)

• Prof. dr. Jan Jacobs (ITM)

Abstract

Salmonella is primarily known as a human pathogen responsible for gastroenteritis. Additionally, certain Salmonella strains pose a severe threat by causing life-threatening bloodstream infections. The emergence of antimicrobial resistance (AMR) in Salmonella has become a critical global concern. The aim of this doctoral research was to investigate the genomic adaptations of Salmonella associated with AMR and explore the transcriptomic changes linked to host adaptation.

Initially, we reviewed the literature on fluoroquinolone resistance (FQR) in Salmonella, and showed that the Salmonella Typhi H58 clade hampers the efficacy of fluoroquinolone treatment for typhoid fever in Asia. A greater diversity of plasmid-mediated quinolone resistance mechanisms was observed in non-typhoidal Salmonella compared to typhoidal Salmonella, likely due to the diverse host niche. Limited whole-genome sequencing (WGS) data on FQR in invasive non-typhoidal Salmonella (iNTS) were found, despite the high burden of iNTS in sub-Saharan Africa.

Subsequently, we conducted a WGS study of Salmonella Concord (S. Concord). This pathogen is predominantly associated with gastroenteritis and bloodstream infections in individuals from Ethiopia and Ethiopian adoptees and exhibits remarkably high levels of AMR. By analysing the genomes of 284 historical and contemporary S. Concord isolates collected from 1944 to 2022, we revealed that S. Concord is a polyphyletic serovar, with isolates belonging to three Salmonella super-lineages. Within super-lineage A, eight lineages were identified of which four were linked to Ethiopia and demonstrated high levels of AMR to most antimicrobials used for treating invasive Salmonella infections in low- and middle-income countries. Using long-read sequencing, we uncovered a patchwork of horizontal gene transfer events in regions harboring AMR genes present on structurally diverse IncHI2 and IncA/C2 plasmids and/or chromosomal islands.

Finally, we re-implemented the iterative comparison of gene co-expression method using the R programming language to assess the extent of gene co-expression conservation between two gene expression datasets. We further investigated the gene co-expression patterns between two S. Typhimurium strains, including a strain representative of S. Typhimurium ST313 from sub-Saharan Africa. Minimal divergence in gene co-expression between the two strains was observed, but transcriptional rewiring likely occurred in the Type Three Secretion System 1 (T3SS-1) which is required for establishing infection in the gut. In conclusion, this PhD research aimed to investigate the genomic adaptations associated with AMR in Salmonella and explore the transcriptomic changes related to host adaptation. The resulting findings contribute to our understanding of AMR and host-adaptation in Salmonella.