Project A05

Mechanisms of infection control by pathogen-educated epithelial-immune cell circuits

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Prof. Dr. Georg Gasteiger & Prof. Dr. Dominic Grün

 

Epithelia, the underlying stromal layers and resident immune cells form functional units that regulate epithelial homeostasis, differentiation, and barrier function. They also provide front-line defence to microbial invasion. Therefore, the multicellular interactions in diverse epithelia-stroma-immune cell units are key determinants of early pathogen elimination versus invasive or persistent infection. Once established during ontogeny, these local cell networks are shaped throughout life by frequent encounters with pathogens that induce pronounced changes in tissue physiology. Intriguingly, exposure of laboratory mice to natural microbiota and pathogens induces changes in the gene-expression programmes, population composition and abundance of resident immune cells that mirror the “immunological state” of human tissues and recapitulate features of human immune responses to infectious and inflammatory challenges (Beura et al., 2016, Rosshart et al., 2019, Reese et al., 2016). While it is clear that this reorganisation of barrier tissues influences the outcome of infections, the underlying mechanisms have not yet been defined.

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Here, we aim to identify the mechanisms of infection control by pathogen-educated epithelia-immune cell units. We will investigate ‘specific pathogen experienced’ (SPE) mice that have undergone a defined series of infections that mimic the “real-world” encounter with frequent human pathogens. We will analyse mechanisms mediating resistance and tolerance to infections, studying viral pneumonia induced by Influenza A virus as well as bacterial infection in skin and lung by Staphylococcus aureus. By combining multiplexed microscopy, single-cell and spatial sequencing analysis with machine learning approaches, we will discover persistent changes of the functional tissue architecture and inter-cellular interactions imprinted through pathogen experience and analyse the resulting effects on cell states within the epithelial, immune, and stromal compartment. 

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Our aim is to map the multicellular spatial and functional organisation of epithelial-immune cell circuits and their “network-response” to infection. Thereby, we will identify the pathways and cellular interactions that confer resistance to infection in pathogen-experienced epithelial barrier organs. As these pathways are naturally shaped by microbial exposure throughout life, we expect that they could be harnessed for the targeted modulation of pathogen defence mechanisms in barrier tissues.