Simmons Group: Intestinal Immunity in Health and Disease
We define how the immune system functions in the intestine to promote health. We uncover the immune pathogenesis of intestinal diseases such as inflammatory bowel disease to develop better ways to treat these disorders.
Our work has provided insight into human intestinal immunity and inflammatory bowel disease (IBD) pathogenesis. We redefined the cellular anatomy of the human intestine identifying new cell types and states linked to intestinal health or inflammation. We identified a new epithelial cell type and defects in goblet cells in severe ulcerative colitis including dysregulation of a goblet cell expressed anti-microbial factor that prevents invasion by commensal bacteria and mucosal inflammation (Parikh et al., Nature, 2019).
While studying the contribution of the intestinal mesenchyme to IBD we identified different fibroblast subtypes that are present in the intestine and defined how their contribution to human hind gut development, adult health and ulcerative colitis (Kinchen et al., Cell, 2018; Fawkner-Corbett et al, Cell, 2021). We described the transcriptional networks that mark each subtype and demonstrate they occupy distinct anatomical locations. These include as crypt, vascular and lymphoid niche cells. These niches are dysregulated in colitis contributing to barrier dysfunction and recruitment and maintenance of pathogenic inflammatory infiltrates (Kinchen et al., Cell, 2018).
We have also defined how the human intestine forms and described the molecular circuits that are sequentially employed to derive the absorptive surface of the gut with all its specialised cells. This work has ramifications for design of advanced human tissue models, congenital intestinal disorders and regenerative medicine approaches (Fawkner-Corbett et al, Cell, 2021).
We addressed the role of immune cells in colitis including CD8+ T cells. The colonic lamina propria houses a vast quantity of tissue resident CD8+ T-cells but their properties and possible contribution to diseases such as IBD had not been well defined. We described their behaviour driving inflammation at mucosal surfaces in IBD and revealed the role of key pro-inflammatory factors they produce (Corridoni et al., Nature Medicine, 2020).
Our group previously defined the functional roles for the IBD susceptibility gene NOD2 in myeloid cells (Cooney et al., Nature Medicine, 2010; Brain et al., Immunity, 2013). We have described innate determinants of defence to invasive Salmonella (Aulicino et al., Nat Comms, 2018).
Our team currently works on several major research directions:
- Immune pathogenesis of intestinal diseases: We utilise multimodal single cell analysis to characterise IBD pathogenesis and translate human IBD genetics to functional biology.
- Human intestinal barrier function: Intestinal epithelia provide a barrier between the microbes within the intestinal lumen and the lamina propria of the intestine, but relatively little is known about their biology and immune functions. We perform large-scale genome and protein interaction screens and imaging-based cellular assays to discover epithelial molecular pathways that regulate intestinal homeostasis. We also study epithelial barrier function in vivo using mouse models.
- Mechanisms of host microbe dialogue in the intestine: Use human tissue and cohorts to define mechanisms employed by host microbes to thrive at the intestinal barrier and define mechanisms of pathogenicity of enteric pathogens such as invasive Salmonellas.
- Human intestinal immunity through life: We are using single cell sequencing and large-scale spatial transcriptomics to map intestinal immune function through the life course. We are developing highly multiplexed spatial approaches to understand cellular niches linked to intestinal health and childhood diseases.
- We test therapeutic hypotheses and develop drug discovery programmes for intestinal diseases: we use a variety of model systems to test therapeutic hypotheses including highly multiplexed advanced tissue models from human cohorts.
Chan Zuckerberg Initiative
Industry Funding: we undertake a variety of industry-funded projects from discovery science to translational work aligned to the WIMM's Therapy Acceleration Lab
National Institute for Health and Care Research
Thames Valley Clinical Research Network
We have the following positions available:
- Wellcome Trust funded post-doctoral scientist positions to explore novel mechanisms of human intestinal barrier function and pathogenesis of inflammatory bowel disease.
- Chan Zuckerberg Initiative post-doctoral scientist position: Examining intestinal immunity through life.
Post-doctoral or PhD scientist positions to investigate metabolic pathways driving barrier homeostasis and inflammation. We will establish histology and imaging pipelines to map human tissues/models at single cell resolution at scale. We will use highly-multiplexed single molecule fluorescent in situ hybridization (smFISH) methods to identify molecular cell types and role of metabolic pathways in immune regulation within intestinal tissue.