This is a full-time, fixed term (4 years) position on Crick terms and conditions of employment.
Project summary and the position
Study of molecular pathways of regulation of the immune response to the pathogens Escherichia coli, Citrobacter rodentiium and the pathobionts Helicobacter hepaticus, Enterococcus faecalis in the gut.
Our laboratory focuses on the study of the regulation of the immune response during immune challenge and infection with either pathogens or pathobionts. The host elicits a pro-inflammatory response to infection which if uncontrolled, can lead to host damage. Our goal is to identify immune cells, pathways and targets of protection and pathogenesis determining disease outcome, with a major emphasis on cytokines, and CD4+ T cells and myeloid cells.
We have published a number of papers leading up to the current projects(s) on the molecular regulation of the immune response with two most relevant examples provided here.
We have discovered that while the transcription factor c-Maf plays a dominant role in regulation of the suppressive cytokine Il10 in CD4+ T effector cells in vitro and in vivo, that c-Maf controls immune responses by regulating disease-specific gene networks and exerts context-specific effects in different experimental mouse models of disease in vivo, through its regulation of other pathways and transcription factors. We showed that c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.
We have recently shown that Blimp-1 (encoded by Prdm1) and c-Maf are co-dominant regulators of Il10 in CD4+ T cells, but also negatively regulate proinflammatory cytokines in effector T cells and yet mice lacking these transcription factors in T cells show no inflammatory pathology. We continue to study c-Maf and Blimp-1 regulation of T cell responses to understand protection or disease progression during intestinal infection with pathobionts and pathogens.
We now wish to compare the immune response to the pathogens E.coli and C.rodentium and to the pathobionts H. hepaticus and E.faecalis, in the gut, using mouse models based on these recent publications and our more recent exciting findings that different transcriptional regulators control different forms of protective immune responses or gut pathology. Specifically, we have shown that another transcription factor Blimp-1 together with c-Maf promotes the expression of Il10 in T-cells while negatively regulating common and unique gene networks of proinflammatory effector molecules. Excitingly, mice with T-cell specific deletion of Prdm1 (encoding Blimp1), Maf or both transcription factors, showed no inflammatory pathology by 28 weeks of age, but upon infection with the pathobiont H. hepaticus we discovered that Blimp-1 and c-Maf protect against different levels and forms of colitis resulting from distinct T cell or neutrophil-mediated pathways, via IL-10-dependent and independent mechanisms (L. Cox; M. Alvarez-Martinez; --- A. O’Garra et al., under re-review). These pathologies resembled different forms of colitis in humans.
Excellent tools are available in the lab and at The Crick, for identifying the pathways and targets determining protection or pathogenesis to pathogens and pathobionts. These include state-of-the art advanced molecular and cellular technologies to study gene expression changes in the tissue and blood, in genetically mutated mice including those with CD4-targetted deletion of Prdm1 and Maf, together with reporter mice expressing these transcription factors. This will facilitate dissection of pathways that regulate the immune response to C.rodentium and E.coli in the gut and the periphery, and to H. hepaticus and E.faecalis in the gut, to define the effector functions resulting in control of the immune response contributing to different forms of pathology in vivo.
The person(s) successful for these position(s) will conduct in vivo experiments in CD4-transcription-factor-targetted gene deleted mice, and reporter mice available in the lab, as well as other relevant genetically mutated mice, and/or with administration of blocking antibodies, to study the pathways and mechanisms of the immune response regulated by these transcription factors which result in the different forms of colitis in response to oral infection with H. hepaticus, as compared to effects during peripheral or oral infection with pathogens. These findings may then be compared with published studies of human colitis.
The aims of this project are to identify pathways of protection or pathology in mice infected orally infected with H. hepaticus. The successful candidate(s) will use cutting-edge state-of-the art advanced molecular and cellular technologies, and will be supported to analyse gene expression changes using RNA-Seq, ATAC-Seq and single-cell-(sc)-RNA-Seq, in the gut and peripheral tissues. The goals are to define immune cells, cytokines and new targets, which contribute to protection, chronic infection and/or immunopathology, which may then be tested for their function in these processes.
This will be in close collaboration with a Senior Lab Research Scientist who strategically organises all gene-deficient mouse colonies and additionally is an experienced molecular immunologist, also expert at isolating and preparing gut tissues from infected mice for pathology, and a Senior Lab Research Scientist who will support and develop immunohistochemistry and advanced histological techniques.
The Research Group
The laboratory focuses on the study of the regulation of the immune response during immune challenge and infection, to identify immune cells, pathways and targets of protection and pathogenesis determining disease outcome. A major programme in the lab continues to be to define transcription factors that regulate cytokine gene expression in myeloid cells and T cells, and their consequent function in experimental mouse models in vivo. Collectively, the aims of the lab are to identify immune cells and pathways contributing to protection and pathogenesis in infectious diseases including factors: (1) leading to or controlling pathology in models of infection of the gut, including with H. hepaticus, E. faecalis and E.coli and C.rodentium; and (2) determining mechanisms of disease outcome in the airways using M. tuberculosis infected TB resistant and susceptible mice where the blood transcriptomic RNA signature resembles human TB disease, and in human TB contacts that control infection or progress to TB.
A unifying theme of the lab is the study of gene expression changes using cutting-edge state-of-the art approaches in the mucosal sites, including the lung and gut, to define immune cells, cytokines and new targets, which contribute to protection, chronic infection and/or immunopathology, using advanced molecular and cellular technologies. In addition to Postdoctoral Fellows, Computational Biologists and Lab Research Scientists, the lab is complemented by clinician scientists, either as Visiting Scientists, or Clinical Collaborators, who play an important role in the lab projects, from providing samples to the development of approaches for molecular study of the immune response in human disease.
The lab uses an extensive set of techniques for studying mucosal immune responses in vivo to infectious pathogens in the blood and tissues, specifically now focussing on the lung and airways (TB) and the gut and periphery (Helicobacter and E. coli) to define immune factors contributing to protection or pathogenesis to infection with pathogens and immunopathology in response to pathobionts. Collectively, the lab members are expert in a broad range of techniques which include:
- Broad range of immunological techniques including flow cytometry
- Immunohistochemistry techniques of lung and gut tissue which are being further developed also to include spatial transcriptomics
- RNA-sequencing (bulk and single cell-RNA-Seq) of blood, whole tissue and/or purified cellular populations
- ATAC-Sequencing to identify transcriptional pathways and targets of immunoregulation during infection
- State-of-the-art bioinformatics techniques to analyse complex data from the above approaches and integrate these data together to link different immune factors, pathways and molecules with disease conditions
Our work is supported by excellent Crick Science Technology Platforms.
You can find the general description of the O’Garra laboratory in this link:
The O’Garra Laboratory of Immunoregulation and Infection, together with the Crick STPs and collaborators will provide an excellent environment for the candidate not only to gain experience in cutting edge state-of-the-art skills, including analysis of complex gene expression changes, to identify immune events in the tissue determining disease outcome, but also to develop their general skills for their future career.
The ability to organise and lead a project independently and to discuss and receive feedback is essential as is the ability to collaborate and work in a team.
Key experience and competencies
The post holder should embody and demonstrate our core Crick values: bold, open and collegial, in addition to the following:
- PhD in in vivo immunology in experimental models - or in the final stages of PhD submission
- Good knowledge and experience in in vivo mouse models
- Technical expertise in immunology
- Evidence of data presentation at scientific meetings
- Experience of experimental design
- Excellent organisational skills
- Ability to work independently to drive through in vivo projects
- Excellent knowledge of the literature
- Capable of interacting and collaborating with diverse lab members within our group
- Experience in flow cytometry
- Experience in microbiology and work in infectious diseases in experimental models such as E. coli, Helicobacter hepaticus or other pathogen/pathobiont
- Experience in immunohistochemistry
- Experience in genomics technologies
- Track record of writing papers as evidenced by publications or submitted manuscripts in refereed journals