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Simmons Group: Intestinal Immunity in Health and Disease

MRC Translational Immune Discovery Unit MRC Weatherall Institute of Molecular Medicine

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.

Scanning electron microscopy (SEM) image of bacteria in the mouse colon
Scanning electron microscopy (SEM) image of bacteria in the mouse colon

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).


cell staining image

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

Selected publications

RESEARCH DIRECTIONS

Our team currently works on several major research directions:

  1. Immune pathogenesis of intestinal diseases: We utilise multimodal single cell analysis to characterise IBD pathogenesis and translate human IBD genetics to functional biology.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

FUNDERS

UK Medical Research Council

Wellcome Trust

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


POSITIONS VACANT

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.

 

CONTACT US

For industry and portfolio feasibility enquiries contact Simona Fourie: +44 1865 231461

Register an interest in involvement in our research in gastroenterology

Related research themes

We use state of the art techniques to interrogate the intricacies of our body’s response to pathogens, cancer and non-communicable diseases. We have particular strengths in T cell signaling, the innate immune system and therapeutic antibody development – particularly in oncology and against pathogens. We have forged strong links with clinical medicine to accelerate translation of laboratory studies into therapeutic strategies.
Immunology and Infection
Understanding the fundamental biology that drives embryonic development and tissue maintenance provides the basis of much of our research into blood diseases, the cardiovascular system and rare genetic conditions.
Stem Cells and Developmental Biology
Building on critical findings from our research streams, we are initiating new drug discovery programmes. Many of our researchers are engaged in target discovery and target validation research – elucidating molecular pathways that can be manipulated for disease modification.
Experimental Therapeutics
We are committed to translating our innovative research into clinical benefit. From new methods of diagnosing chronic conditions, to finding the latest treatments for diabetes, cancer, heart disease, stroke and rare diseases, our department is involved in hundreds of clinical studies every year.
Clinical Studies and Trials
Employing a range of genetic techniques, we probe the fundamental causes of disease. Our expertise spans identification of causative genes in rare inherited diseases, through to elucidating complex gene regulatory pathways and exploration of susceptibility to common disease through genome-wide association studies. We use cutting edge techniques to manipulate the genome to determine how particular genes work and study how variants in regulatory DNA may contribute to common disease. An important overall aim is to improve the management of human genetic diseases.
Genetics, Genomics and Genome Biology
We have cutting edge expertise in a range of statistical and mathematical modelling techniques that allow us to interrogate large data sets – from the ‘big data’ of genomics through to magnetic resonance imaging and clinical trials. We are also home to the Medical Research Council WIMM Centre for Computational Biology – a hub for accelerating progress in genomics analysis and single cell biology.
Computational Biology, Statistics and Bioinformatics
We seek to bridge the ‘innovation gap’ between ‘basic’ research in the laboratory and tangible benefits for patients. Our researchers aim to develop novel approaches to treating disease and we have particular strengths in evaluating technologies such as antibody therapy and gene therapy, and using new techniques for target discovery. Many of our researchers collaborate with biotech and industry partners to accelerate progress along the drug discovery pipeline and assess these new treatments in the clinic.
Emerging Therapies and Drug Discovery
A raft of cellular and molecular biology techniques underpin much of the work we do to elucidate the mechanisms of disease. We use established techniques to answer new questions and also develop our own novel and unique methodologies to drive further innovation.
Cellular and Molecular Biology