WIMM PI
CURRICULUM VITAE
Personal data
Name:
Email:
Alison Simmons
alison.simmons@ndm.ox.ac.uk
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 downregulation 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 fullblown 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 DCSIGN 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)
Investigation of the function of Crohn disease accessory genes
(£200,000)
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.
Teaching
Bedside/endoscopy and lecture-based clinical teaching of SpRs/medical students, graduate
students. Run Oxford graduate entry gastroenterology preclinical course. Past MSc
students-Monika Mortensen, Tobias Brode, Georgios Sogkas, Marios Tsouksakis.
Career development of lab members
DPhil students in my group have gone on to postdoctoral fellowships (Dr Pichulik in Dr
Weber's lab, Tubingham); fast-track medicine (Dr Katherine Sharrocks); consultant
gastroenterologist (Dr Rachel Cooney); ongoing specialist Gastroenterology training (Dr
Oliver Brain). Wellcome funded post-doctoral fellow Dr Ben Owens won BBSRC young
entrepreneur award, set up Stromal cell Society of British Society of Gastroenterology and
organized first national meeting 2012. Gates funded post-doctoral fellow Dr Alasdair Leslie
has moved to set up own group in a Howard Hughes funded position at KwaZulu-Natal
Research Institute for Tuberculosis and HIV, Durban. Surgical Fellow Sam Sharma has won
a Fulbright Scholarship award for study at the Rockefeller University 2013.