GENOMIC RESEARCH LABORATORY

SCHRENZEL Team

Our major research axes address different clinical challenges related to bacteria colonizing the human body, using metataxonomic, metagenomic and genomic approaches, which rely on next-generation sequencing (NGS).

The metataxonomic approach is based on sequencing of phylogenetic/taxonomic markers (mostly the 16S rRNA gene) while metagenomics uses random sequencing of DNA directly recovered from samples. Our studies aim to identify associations between taxonomic composition and various diseases (such as cancer, infections, neurologic, hepatic and renal disorders) or exposure to specific treatments (including probiotics, antibiotics and other medications, intensive care, dietary factors, etc.). Beyond taxonomic composition, we explore gene functions, with a particular emphasis on antibiotic resistance. Our projects predominantly focus on the microbiota of the intestine, oral cavity, and respiratory system. Our second major focus is clinical metagenomics in the context of infectious diseases. This involves utilizing NGS and bioinformatics tools to identify DNA fragments from pathogenic microorganisms, particularly bacteria and fungi, in clinical samples. Our efforts in this domain are dedicated to (i) optimizing procedures for selectively eliminating human DNA from clinical samples, aiming to enhance the pathogen-to-human DNA ratio and provide a more comprehensive characterization of the microbiota members; (ii) quantifying pathogens using calibrators, such as cells from organisms not part of the human microbiota; and (iii) refining reference databases and automating bioinformatics pipelines for the analysis of NGS data.

Genomic studies of pathogen isolates of interest, based on NGS, provide the highest resolution for molecular typing and enable the identification of acquired antibiotic resistance genes and the presence of mutations conferring resistance. This approach allows for addressing genetic and phylogenetic relatedness between strains, which may help in identifying potential routes of spatial and temporal transmission of strains and their antibiotic resistance determinants during outbreaks in hospitals or communities, or on a broader scale, such as transmissions to humans from animals, foods, or the environment. We actively participate in the working group involved in the development of the Swiss Pathogen Surveillance Platform (SPSP.ch), whose aim is to harmonize NGS practices within Swiss clinical microbiology laboratories and implement a molecular surveillance platform allowing integration of high-resolution whole genome sequencing (WGS) typing data and epidemiological information. Additionally, we are members of the IICU Consortium (Personalized, data-driven prediction and assessment of Infection-related outcomes in Swiss ICUs), a collaborative initiative set to transform the landscape of predicting infection-related outcomes in intensive care units.

FRANCOIS Team

Staphylococcus aureus is an important human pathogen evolving rapidly in response to environmental stress. Approximately 20 to 30% of the general population carry asymptomatically Staphylococcus aureus but the bacterium is also responsible for various acute or chronic infections often severe. Originally detected exclusively in animals and in pig farmers in Europe, Staphylococcus aureus belonging to CC398 lineage has become a major pathogen prevalent in the human clinic worldwide, in only one decade. From ongoing annual surveillance program we noticed that CC398 prevalence in still increasing as well as the severity of infections even in patients living without contact with animals. Very recently, our group and different colleagues from various countries reported numerous cases of highly resistant and virulent isolates illustrating that clonal expansion and evolution is still ongoing in the CC398 lineage. From important sequencing efforts our group showed that sequential acquisition of mobile genetic elements including temperate bacteriophages are responsible for this evolution. Recently, we published findings showing that prophages modulated expression of various virulence factors at the transcriptional level and contributed to bacterial virulence and that prophage content modulated genome plasticity and contributed to the adaptation of animal populations towards a clinically prevalent lineage. In vitro experiments allowed us to transfer prophage of interest in naïve isolates (non-pathogenic) to document that the presence of prophage was sufficient to modulate expression of virulence factors and contributed to increase the pathogenicity of strains. The mechanisms involved the alteration of saeRS transcription and subsequent expression of bacterial adhesins. Indeed, we showed that the genes of the two-component regulatory system SaeRS are overexpressed in the strain containing prophages, as well as several genes involved in bacterial virulence belonging to the SaeRS regulon. Mutation in saeR is drastically reduced the prophage-driven increased capacity to adhere to human fibronectin and to invade human non-phagocytic cells. This alteration is not related to a difference in mRNAs stability as shown in mRNA decay experiments. We are identifying the gene from bacteriophage origin mediating the increase in bacterial virulence through action on the expression of important global regulator.