WIMM PI
CURRICULUM VITAE
Personal data
Name: Alison Simmons
Email:
Current Post
2009-Clinical Senior Lecturer and Honorary Consultant in Gastroenterology
Translational Gastroenterology Unit, John Radcliffe Hospital and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, Oxford.
Summary of previous posts
2003-2008-MRC Clinician Scientist and Honorary Consultant in Gastroenterology-Oxford
1998-2002-MRC Clinical Training Fellow and SpR gastroenterology-Oxford
1995-1997-Registrar in Hepatology/Gastroenterology Royal Free and Addenbrookes
Research Achievements
Describe main research achievements to date
I undertook a PhD (1998-2002) funded by an MRC clinical training fellowship in Professor Sir Andrew McMichael’s lab in the Weatherall Institute of Molecular Medicine in Oxford. Here I focused on HIV-1 pathogenesis investigating the function of HIV-1 Nef. Nef is one of the HIV-1 accessory genes shown to be a key pathogenicity factor in humans and animal models. Nef is expressed early in the HIV-1 life cycle where it interacts with signaling molecules in CD4+ T cells, the major reservoir of HIV-1 in vivo. I found Nef functions to increase HIV-1 replicative capacity in CD4+ T cells by triggering a signalling path mimicking CD4+ T cell activation via anti-CD3, inducing key host cell factors required for viral replication (Simmons et al., Immunity 2001). Following this period I won an MRC Clinician Scientist award (2003-2008) I went on to investigate the molecular mechanism by which Nef signals in T cells. I conducted a proteomic analysis of CD4+ T cell signaling compartments and found Nef positively regulates signaling by interfering with ubiquitination and destruction of key CD4+ T cell signalling molecules, such that their activity is increased in infected CD4+ T cells (Simmons et al., Immunity 2005).
Since becoming independent I have worked on innate immune signalling, specifically in delineating mechanisms of self- non-self- recognition of pathogen recognition receptors (PRRs) in both infectious and inflammatory disease. My lab have used genomic and proteomic approaches to investigate signaling through PRRs expressed on antigen presenting cells. We described the basis of signaling though the C-type lectin DC-SIGN, used by HIV-1 as an entry receptor to DCs, where it can escape degradation in lysosomes to be released as intact virions in a more infectious form to bystander CD4+ T cells. We found DC-SIGN activation leads to a tolerogenic expression profile in DCs, differing from other PRRs such as the Toll-like receptor large scale gene expression profiles, with down-regulation of surface MHC class II, co-stimulatory molecules and interferon response genes. We found DC-SIGN signals via a Rho-LARG (ARHGEF12) pathway important for HIV-1 replication and viral synapse formation (Hodges et al., Nature Immunology 2007).
My laboratory have recently investigated the function of the intracellular PRR NOD2 in dendritic cells and shown NOD2 can activate autophagy in a manner requiring ATG16L. We were the first to link two of the major Crohn’s disease susceptibility genes in a single functional pathway in human antigen presenting cells. We found NOD2 mediated autophagy is required for MHC class II antigen presentation and bacterial handling in DCs, and that variants of NOD2 expressed in Crohn’s patients antigen presenting cells show defects in autophagy induction, bacterial handling and MHC class II antigen presentation (Cooney et al., Nature Medicine 2010). In Crohn’s disease there is abnormal immune reactivity to the commensal gut flora and defective autophagy induction, bacterial clearance and antigen presentation would provide a mechanism to trigger inflammation in this disease. We have also investigated how NOD2 signals in DCs to regulate miRNA expression and found NOD2 induces the miR-29 family to control IL-23 levels at the end of an immune response in a manner defective in Crohn’s (in review, 2011). We are now using the information obtained from these studies to guide development of new therapies for Crohn’s.
What are the Future Aims of Your Current Group?
Please outline the main questions your group is addressing over the next 5 years (max 300 words)
We aim to define new mechanisms of self non-self recognition by the innate immune system. While there has been much progress in understanding innate immune recognition at a molecular level, with the description of several families of pattern recognition receptors (PRRs) with roles in antimicrobial and inflammatory responses, there remains much to learn about the specific function of individual receptors, and how they signal in combination to direct appropriate innate and adaptive immunity. As symbionts and pathogens produce similar molecular patterns that are sensed by PRRs, the mechanisms by which the immune system differentiates between commensal and infectious agents are unknown. As part of this work we have undertaken detailed analysis of signaling cascades induced by individual PRRs in human antigen presenting cells to understand how each receptor functions and why each has been conserved through evolution.
Some examples of ongoing projects as a result of this work include:
1) Defined new mediators of NOD2 signaling including Drp1, a mitochondrial fission protein with the potential to link multiple IBD susceptibility genes in a single functional pathway. We are exploring the role of NOD2 mediated Drp1 activation in autophagosomal membrane generation, localization of mitochondria at the autophagosome for provision of ROS, inflammasome activation, programmed cell death and bacterial handling.
Drp1 hypomorphic mice have dilated cardiomyopathy, and we find increased inflammatory mediators in cardiac muscle of these mice. We are exploring whether defective mitophagy in Drp1 hypomorphic cardiomyocytes leads to abnormal PRR/inflammasome triggering, perhaps as a result of accumulation of defective mitochondrial DNA.
2) We have used quantitative phosphoproteomics to define the function of TLR8. In collaboration with Dr Alex Weber we have found the 2 known ligands for TLR8, ssRNA40 and R848 signal differently in human DCs with different functional outcome and defined the molecular determinants of this recognition. R848 is an imidazoquinolone, one of a family of small molecules used in the clinic to treat skin cancer, viral skin infections and in clinical trials as a cancer vaccine adjuvant. We are exploring the role of proteins we found recruited on R848 treatment of DCs in the mechanism of action of this class of drugs. For example we found TLR8 activation by R848 activates Rcl, a 5'-monophosphate-2'-deoxyribonucleoside hydrolase. We are exploring the role of this enzyme in handling/recycling of viral and bacterial nucleic acid in DCs.
3) Quantitative phosphoproteomics has shown unexpectedly diverse PRRs activate DNA repair proteins in human DCs. we are investigating whether PRRs are activate DNA repair paths normally to protect against stress induced reactive oxygen species and other toxic metabolites produced as a by product of anti-bacterial/viral innate immune responses. Should this prove to be the case we intend to explore the role for this activity in prevention of inflammation associated cancer
Lay Summary of Research
Please summarise (max 300 words) what you are trying to achieve in your research in a way that could be understood by any intelligent member of the public.
We work on understanding the function of the most evolutionary primitive part of the immune system, the innate immune system that controls the decision whether or not to activate a full-blown immune response when an individual is exposed to an infection. We are investigating the function of the innate immune proteins that make up this system that sense key motifs present on infectious microbes. These proteins control the nature of the ensuing immune response.
Advances in genome research have demonstrated key defects in these innate sensors in diseases such as Crohn’s. Crohn’s is a major inflammatory bowel disease affecting 1:1000 of the UK population. The disease results from a breakdown in the innate immune system’s ability to recognise gut microbes as normal. Treatment for Crohn’s is relative ineffective in a significant proportion of patients and the disease places a heavy socio-economic burden on western health care systems; there is a pressing requirement to develop improved more targeted therapies in the disease.
We are defining pathways in which innate sensors operate normally and comparing how these are disrupted in inflammatory diseases such as Crohn’s, or how these pathways are usurped by pathogens, to find molecules that could be specifically be targeted to design drugs to reverse these pathway defects.
Publications
Simmons A, Aluvihare V, McMichael A. (2001). Nef triggers a transcriptional program in T cells imitating single- signal T cell activation and inducing HIV virulence mediators. Immunity 14, 763-77.
Simmons A, Gangadharan B, Hodges A, Sharrocks K, Prabhakar S, Garcia A, Dwek R, Zitzmann N, McMichael A. (2005). Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling. Immunity 23, 621-34.
Cebere I, Dorrell L, McShane H, Simmons A, McCormack S, Schmidt C, Smith C, Brooks M, Roberts JE, Darwin SC, Fast PE, Conlon C, Rowland-Jones S, McMichael AJ, Hanke T. (2006). Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers. Vaccine 24, 417-25.
Hodges A, Sharrocks K, Edelmann M, Baban D, Moris A, Schwartz O, Drakesmith H, Davies K, Kessler B, McMichael A, Simmons A. (2007). Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nature Immunology 8, 569-77.
Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010). NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine 16, 90-7.
Brain O, Allan P, Simmons A (2010). NOD2-mediated autophagy and Crohn disease. Autophagy 3, 6 (3). Holger B. Kramer, Kerry J. Lavender, Li Qin, Andrea R. Stacey, Michael K.P. Liu, Katalin di Gleria, Alison
Simmons, Nancy Gasper-Smith, Barton F. Haynes, Andrew J. McMichael, Persephone Borrow and Benedikt M. Kessler (2010). Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 Infection. Plos Pathogens 6, 6 (5):e1000893.
Simmons A (2010) Crohn's disease: Genes, viruses and microbes. Nature 466, 699-700.
Ranasinghe S, Kramer H, Wright C, Kessler B, di Gleria K, Gillespie G, Blais M, Culshaw A, Pichulik T, Simmons A, McMichael A, Rowland-Jones S, Dong T. The Antiviral Efficacy of HIV-Specific CD8+ T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate. PLoS Pathogens 7(5): e1001341 (2011).
Functional consequences of mutations in the autophagy genes in the pathogenesis of Crohn's disease. Brain O, Cooney R, Simmons A, Jewell D. Inflamm Bowel Dis. 18, 778-8 2012.
Guidelines for the use and interpretation of assays for monitoring autophagy. Daniel J. Klionsky,1,2,3,* et al., Autophagy. 8, 445-544 2012
Intestinal stromal cells in mucosal immunity and homeostasis. Benjamin M. J. Owens and Alison Simmons. Accepted, Mucosal Immunology. 2012
Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Mayer A, Steevels T, Jewell D, Simmons A. NOD2 induces the microRNA-29 family to control IL-23 release from dendritic cells in a manner defective in Crohn’s disease. In final review, Immunity. 2012
Elif Colak*, Alasdair Leslie*, et al., RNA and Resiquimod are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate intracellular signaling. In revision, Embo molecular med 2012.
Research funds 2006-2012
2006 Action Medical Research Clinical Training fellowship (Rachel Cooney) (£200,000)
Investigation of the function of Crohn disease accessory genes
2006 MRC studentship (John Baker) (£200,000)
NOD2 signaling in dendritic cells
2007 NACC/CORE Clinical Training fellowship (Oliver Brain) (£250,000)
Identification of NOD2 signaling complex in human antigen presenting cells
2007 MRC studentship (Tica Pichulik) (£150,000)
HIV-1 signaling in dendritic cells
2008 Fondation Philippe Weiner Maurice Anspach (Benedicte Danis) (£100,000)
Function of host cell genes facilitating HIV-1 progression
2008 Oxford Wellcome Clinical Training fellowship (Philip Allan) (£250,000)
Mechanism of NOD2 and inflammasome cross-talk
2008 Wellcome Clinical Training Fellowship (Elham Khatamzas) (£350,000)
HIV-1 escape from innate immunity in early infection and in mucosal associated lymphoid tissue
2009 HEFCE Senior Clinical Lecturer Award (£500,000)
Innate immune pathways in infectious and inflammatory disease
2009 Oxford NIHR BMRC funding (Peter Simpson) (£250,000)
Investigation of the extent to which autophagy pathways are defective in Crohn Disease
2010 Vertex Research Grant (£100,000)
Identification of cellular factors involved in NOD2 mediated autophagy
2010 Bill and Melinda Gates foundation co-applicant with Professor Hubbell (EPFL) £1,900,000)
Nanoparticulate delivery vaccine adjuvants and immune priming in lymphoid tissue
2010 Fondation Philippe Weiner Maurice Anspach (A Mayer) (£100,000)
HIV-1 infection in gut mucosal cells
2010 Wellcome Trust project grant (£250,000)
Mechanism of NOD2 mediated autophagy
2010 IOIBD ($50,000)
Autophagy pathways in mucosal cells in IBD
2010 Marie Curie fellowship (Tessa Steevals) (£200,000)
Information processing of commensal bacterial products by mucosal dendritic cells
2011 Wellcome Clinical Training Fellowship (Mr Sameer Sharma) (£250,000)
Mechanism of intracellular sensing and cross-talk between NLRs
2011 Sir Jules Thorn Award (£1,250,000)
Defining Druggable Targets in Crohn’s
2012 WIMM MRC studentship (Mr Daniel Gaughan) (£200,000)
Mechanisms of nucleic acid sensing and signaling in dendritic cells
2012 Oxford biomedical research centre funding (Dr Mei-yi Sun) (£200,000)
Stratification of the Oxford IBD cohort
2012 NDM studentship/Rhodes scholar (Dr David Walcott) (180,000)
Secretory pathway function of NOD2 in intestinal mucosal cells
2013 Oxford Wellcome Clinical training fellowship (Dr Tom Chapman) (£200,000)
Role of Drp1 in bacterial handling by innate immune receptors
Examples of invited speaker
2009-Keystone Symposia-HIV immunobiology-from infection to immune control
2010-DC 2010: forum on vaccine science. 11th international symposium on dendritic cells in fundamental and clinical immunology
2011-15th International Congress of Mucosal Immunology
2012-Keystone Symposia-Viral Immunity and host gene influence
Other professional activities
Ad hoc reviewer of grants and fellowships for funding bodies including MRC, Wellcome Trust, NACC/CORE (Digestive Diseases Charity), National Institute of Health Research, The Broad Foundation, Singapore Immunology Network
Ad hoc reviewer for journals including Nature, Nature Medicine, Immunity, Journal of Immunology, European Journal of Immunology, AIDS, Virology, Lancet, Journal of Clinical Investigation, Proceedings of National Academy of Sciences, USA, Gastroenterology, Journal of Infectious disease.