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Typas Group

Systems microbiology

The Typas group develops high-throughput approaches to study bacterial cellular networks in the context of their interactions with each other and their environment.

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Previous and current research

In recent years, the explosion of sequencing efforts has provided a glimpse in the diversity of microbes that live on this planet, and the enormous functional potential they encode. We develop high-throughput quantitative approaches to shed light into gene function and organization in bacteria (figure 1). These approaches involve combining reverse genetics with quantitative genome-wide readouts to link genes to phenotypes and/or to known functional modules, such as pathways and protein complexes. We then use the data as starting points to generate mechanistic insights into targeted cellular processes, and to understand how function, regulation and cross-talk between cellular processes changes across evolution, impacting the phenotype.

Our main biological focus is on the bacterial envelope – its assembly, organization and ability to sense and transmit information. Working at the intersection between systems-based approaches and molecular mechanism, we have discovered key missing players of cell wall biosynthesis, established that conserved envelope machines are regulated and cross-talk in a rapidly evolving manner, and uncovered signalling pathways that the cell uses to monitor envelope defects. The cell envelope is how bacteria sense and interact with the environment, but also what protects them from external insults, such as antibiotics. This natural connection to antibiotics, has initiated to large line of research in the lab towards devising new strategies to target resistant pathogens and to solve current bottlenecks in antibiotic discovery. In the past, we have systematically profiled drug interactions in prominent Gram-negative and Gram-positive bacterial species, uncovering general principles that govern drug interactions and numerous synergies that are effective against clinical isolates of difficult to treat pathogens. We have also developed proteomics-based (together with the Savitski team) and chemical-genetics based ways to identify the mode-of-action of drugs, and their interaction at the resistance level (cross-resistance and collateral sensitivity).

We have also recently moved our efforts to developing automated platforms and genome-wide approaches to study: a) the human gut microbiome and b) host-pathogen interactions. Over the past few years and together with the Bork, Patil, Zeller and more recently Zimmermann labs at EMBL, we have established systematic cultivation and phenotyping pipelines for the human gut microbiome. We have then used these in vitro microbiomics pipelines to study extensively the interactions of pharmaceuticals with the human gut microbiome (Figure 2), unravelling an unexpectedly high impact of non-antibiotic drugs on human gut microbes, a mechanism by which bacteria store drugs intracellularly, ways to mitigate the collateral damage of antibiotics to the gut microbiome, and emergent behaviours of communities to drug treatment. In the host-pathogen interface, we have used Salmonella as our model organism, to perform the first systematic host-pathogen protein-protein interaction study in the context of infection, map the host response during infection – unravelling a new role of cathepsins in cell death, and devise a labelling strategy to selectively and directly measure Salmonella’s metabolic fluxes during proliferation inside host cells.

Future projects and goals

We are broadly interested in the impact of mutations and horizontal gene transfer in the evolution of bacterial cellular networks. To tackle this, we are focusing on systems-based approaches in the E. coli pangenome and in related enterobacteria. On the drug front, we are interested in discovering novel ways to target pathogens, and in understanding and mitigating antibiotic resistance. Capitalizing on our unique in vitro “microbiomics” platforms, we aim to move some of our systems based approaches to abundant and key gut microbiota species, which still remain terra incognita. Together with 15 other labs at EMBL (and alumni) and as part of the Microbial Ecosystems Transversal Theme, we are working towards generating the tools, resources and functional information required for establishing from scratch new model species for the human gut microbiome. We are also expanding our experiment pipelines to be able to study the dynamics and properties of personalized microbiome communities, and aim to devise strategies for targeted strain replacement within them. This know-how, resources and automated pipelines will move in a new facility being established at EMBL on Microbial Automation and Culturomics.

In the host-pathogen front, our efforts have more towards understanding the tug of war that takes place between bacteria and phages. Building on our recent discovery of a new bacterial immune system and our know-how on host-pathogen interactions, we plan to use systematic genetic and biochemical approaches to understand the mechanisms, diversity and evolution of this complex and fascinating interface. In the long run, understanding bacterial immunity can open new doors for fighting bacterial pathogens by exploiting their internal weapons.

Figure 1: High-throughput reverse genetics provide insights into the gene function and drug mode-of-action (Typas et al., Nat Methods 2008; Typas et al., Cell 2010; Nichols et al., Cell 2011; Kritikos et al., Nat Microbiol 2017; Koo et al., Cell Systems 2017; Galardini et al., eLife 2017; Brocahdo et al., Nature 2018; Banzhaf et al., EMBO J 2020; Mateus et al., Nature 2020; Bobonis et al., Nature 2022; Viéitez et al. Nat Biotech 2022; Galardini et al., Mol Sys Biol 2022; Cacace et al., Nat Microbiol 2023; Sakenova et al. biorXiv 2024).
info graphic showing an overview on the drug–microbiome–host triad and their interactions
Figure 2: Drugs can impact the microbiota composition, but microbes also affect drug efficacy (Maier et al., Nature 2018; Maier et al., Nature 2021; Klünemann et al, Nature 2021; Garcia-Santamarina et al., biorXiv 2023).
Figure 3: Systematic approaches the host-pathogen interface contributes to mapping the host targets of effectors Salmonella secretes during infection, the metabolites Salmonella uses in the host, and the dynamic host response during infection (Selkrig et al. Nat Microbiol 2020; Walch et al. Cell Host Microbe 2021; Mitosch et al. Plos Biol. 2023).

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