Cambridge Instit ute for Therapeuttic Immunology
& Infectious Disease
Institute Directory CITIID CITIID
www.citiid.cam.ac.uk A PERFECT L O C A T I O N
The Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID) was established by the Department of Medicine to support both fundamental and translationaal research on human disease.
CITIID houses up to 250 scientists working in research groups focussed on understanding the pathogenesis and improving the management of immune‐related disorders, as well as transforming our understanding of how infectious agents interact with humans. Later in this directory you’ll find out more about these studies.
There is also a strong focus on health issuess of global importance, and on antimicrobial resistance. In particular, we work closely with key overseaas partners including universities, agencies and industry to ensure that we can increase our global impaact in a coordinated programme.
CITIID brrings together geographically dispersed groups working on immunity and infection across the Cambridge Biomedical Campus, the largest Biomedical campus in Europe. By encouraging research at the clinical interface, for example in the Cambridge Clinical Research Centre and with industry, CITIID also faciilitates the translation of scientific disscoveries into clinical benefits.
Its location on the Cambridge Biomedical Campus places CITIID at the centrre of the Cambridge Cluster where it benefits from the closeness of several other major health‐related organisations such as the Royal Papworth Hospital, MRC‐Laboratory of Molecular Biology, CRUK Cambridge Institute and Astra Zeneca’s global research and development headquarters.
CITIID transforms immunity and infection research in Cambridge by providiing researchers with advanced facilities that enable them to optimise their work on understandding human immune, inflammatory and infectious diseases. By bringing together its clinical capabilities and key industry partners, CITIID is also well‐placed to drive therapeutic breakthroughs, improove patient outcomes and advance population health both in the UK and abroad.
1 O U R S C I E N C E
Designed to Lead Developments in Autoimmunity
CITIID is already driving therapeutic breakthroughs in immune‐related diseases such as inflammatory bowel disease, type‐1 diabetes, vasculitis annd systemic lupus erythematosus. The incidence of such disease is rising worldwide at a truly alarming rate and collectively they represent a major global public health issue. We study what drives these diseases – how they develop and evolve, and how they cause harm to humans – and use this understanding to develop new therappeutic strategies that can be translated quickly and safely to patiennts worldwide.
A key strength of CITIID is that immune‐mediated disease is studied alongside innfectious disease. The human immune system has evolved to defend us against the dangerous microorganisms that cause disease; autoimmunity and inflammatory diseases are caused when this defence mechanism malfunctions. Crucially, a dysfunctional immune system uses the same molecular pathways and mechanisms as a healthy immune system uses to fight infection, which means vital insights emerge from tackling infectious disease and autoimmunity together.
Over the last four years scientists at CITIID have established a whole genome sequencing‐based programme to investigate undiagnosed primary immunodeficiency. This has provided over three hundred diagnostic reports, uncovered many genes associated with primary immunodeficiency, and allowed the genetic variation in the development of these diseases to be explored.
2 O U R S C I E N C E
Designed to Combat Multi‐Drug Resistance
Antimicrobial resistance is one of the biggesst threats to global health and internaational food security. Scientists at CITIID develop novel approaches to overcome this challenge.
Considering how human genetics responds to infection is a key component in understanding the role of the microbiome in health and disease. By using cutting‐edge scientific metthods to monitor the spread oof antimicrobial resistance, our scieentists can even use historical data to understand the spread of multi‐drug resistance long after an outbreak. Such studies have an eenormous impact on our ability to manage the continued spread of a disease and allow us to anticipate future threats.
A Centre for Global Answers
Infectious disease, antimicrobial resistance and autoimmunity are three of hummanity’s deadliest foes and are major global challenges. Cambridge is one of the world’s leading research universities, working across disciplines with international partners to find solutions to manage and eradicate these threats.
CITIID is at the centre of efforts to understand the spread of disease. We have researchers working in countries across the globe, meaning we have a very real understanding of the iimpact diseases have on patients. Many of our projects are in third world countries where socio‐ecoonomic factors make the impacts of these diseases even greater.
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The Jeffrey Cheah Biomedical Centre was established in 2016 with funding ffrom the Higher Education Funding Council for England (HEFCE) UK Research Partnership Infrastructure Fund (UKRPIF), the Univversity of Cambridge Capital Fund, and philanthropic donations. The majority of our researchers are located in this state‐of‐the‐ art facility on the Cambridge Biomedical Campus.
FROM CONCEPT IN 2016
TO COMPLETION IN 2019
5 6 CITIID CITIID
OUR SCIENTISTS
Steve Baker Studies the microbiology, genetics, epidemiology and treatment of enteric infections in 10 developing countries.
Allan Bradley Is strongly focused on using genetics to discover genes involved in various biological 11 systems.
Elisabeth Busch‐Nentwich Explores molecular phenotypes through the transcript sequencing of whole vertebrate embryos and tissues. 1 2 Sarah Caddy Studies how rotavirus is targeted by antibodies, focusing on vaccination and maternal 13 immunity.
Menna Clatworthy Is interested in the humoral immunity in humans, how this goes wrong in disease and 1 4 how this can be manipulated therapeutically using experimental medicine studies.
Gordon Dougan Undertakes research focused on the genetic analysis of host/pathogen interactions 15 during infection, particularly those involving enteric bacteria.
Ravindra Gupta Focuses on drug‐pathogen and host‐pathogen interactions to inform successful global HIV 1 6 control/cure strategies.
Christoph Hess Studies the molecular basis of how cellular metabolism is regulated, and itself 1 7 regulates, immune‐function in healthy and disease states.
David Jayne Conducts clinical trials and associated biomarker work in primary systemic vasculitis and 1 8 systemic lupus erythematosus.
Nicole Kaneider Investigates GPR35’s function, and in particular the communication of immune cells 19 expressing this receptor, and their environment.
Arthur Kaser Investigates the mechanisms that underlie inflammation at mucosal surfaces. 2 0
James Lee Studies the genetic associations in immune‐mediated disease by combining genetics, 21 genomics, molecular biology and immunology‐based approaches.
Paul Lehner Works on functional genetic and proteomic technologies to identify novel genes and 2 2 therapeutic approaches in virus:host interaction.
6
Florian Marks Operates a network of field sites capable of conducting multi‐center epidemiological field 23 studies for basic research and clinical trials
Nick Matheson Studies host‐virus interactions to provide insights into viral pathogenesis, cell biology, 24 and novel therapeutic approaches.
Eoin McKinney Studies aberrant immune response to indicate novel tests and/or interventions that can 25 help clinicians treating immune pathology.
Yorgo Modis Our overarching goal is to gain a mechanistic understanding at the molecular level of how 26 the cell detects cytosolic viral RNA and how it silences viral gene expression.
Ankur Mutreja Uses advanced bacterial genomics and metagenomics to better understand the 27 evolution and spread of pathogens.
James Nathan Gains novel insights into oxygen and metabolite sensing pathways, providing potential 28 new therapeutic targets for inflammatory disease and cancers.
Virginia Pedicord Seeks mechanistic insights into the influence of commensal microbes on local and 29 systemic immune responses.
Lalita Ramakrishnan Researches the pathogenesis of tuberculosis, and tries to understand both host and 30 pathogen strategies that can interact to result in clearance or disease.
John Sinclair Studies the molecular basis of viral latency and reactivation and how the host immune 31 response combats viral disease.
Ken Smith Combines genomics, immunology and clinical medicine to analyse the regulatory 32 mechanisms underpinning immune‐mediated disease and develop diagnostic tools.
Alex Taylor Is evolving and engineering synthetic genetic polymers, xeno nucleic acids (XNA), as novel 33 tools for reprogramming biology and precision medicine.
Chris Wallace Develops statistical methods and uses integrative statistical analysis of genomic data to 34 improve diagnosis and treatment of immune mediated diseases.
Mark Wills Is interested in the immunobiology of HCMV in lytic and during latent infection, and how 35 the pathogen persists for the lifetime of its human host. 7 OUR IMPACT
Much of the research undertaken in CITIID has a focus on real‐life challenges. As such, it has a significant positive impact on the people’s lives.
The stories below describe some examples of the impact that our research has on a daily basis.
From genetic analysis to personalised medicine in inflammatory bowel disease. Our research found a transcriptional signature that is detectable within peripheral 36 blood and correlates with long term clinical outcome in IBD.
New treatments for Tuberculosis. Our researchers revealed that the actively‐growing bacteria induce bacterial efflux 38 pumps that could be therapeutic targets using existing drugs.
The immunity of inflammatory bowel disease is exposed. Our researchers developed experimental methods for examining the 40 environmental stresses and microbes that could be responsible for triggering IBD.
Improving sanitation in rural Africa. Our researchers are providing evidence that simple behavioural changes can improve 42 the health of rural communities in the third world.
Cholera: a global challenge. Our researchers are using information locked within the genomes of historic cholera 44 samples to predict the spread of past cholera pandemics throughout Africa.
8 CORE FACILITIES
CITIID offers a range of core facilties to it’s researchers and the wider scientific community. Some of these are listed below, and our facility contacts are more than happy to discuss your specific needs.
NIHR Cambridge BRC Phenotyping Hub Equipped with state‐of the art equipment including high speed cell sorters, bench top 46 analysers, microscopes and high content/high throughput equipment.
Imaging Offering a variety of instruments and analysis techniques. 47
Computing High‐performance computing (HPC) cluster and 200TB network storage that is 47 configured similar to the University of Cambridge HPC
Immuno‐metabolism Offering cutting‐edge, high‐resolution liquid chromatography mass spectrometry (LC‐MS) 48
Bio‐Safety Level 3 CL‐3 containment facilities for working with non‐attenuated clinical organisms 48
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We are sstrongly focused on using genetic manipulation to discover the genes invvolved in various biological systems, using somatic mutagenesis in mice to discover cancer genes and genetic screens in ES cells in culture
Allan is also a serial entrepreneur and has established several biotechnology companies. While in the USA he founded Lexicon Pharmaceuticals Inc. that is publicly traded, and Spectral Genomics Inc. that was later acquired. In the UK he founded Kymab Ltd.. in 2010, and Petmedix Ltd. in 2017. PUBLICATIONS
Revealing hhidden complexities of genomic rearrangements generated with Cas9. Boroviak K, Fu B … Bradley A; Scientific Reports 2017; DOI: 10.1038/s41598‐017‐12740‐6
Bradley Comprehensive annotation and evolutionary Bradley insights into the canine (Canis lupus familiaris) antigen receptor loci. Martin J, Ponstingl H … Bradley A; Immunogenetics 20188; DOI: 10.1007/s00251‐017‐1028‐0
Molecular synergy underlies the co‐occurrence patterns and phenotype of NPM1‐mutant acutte myeloid leukemia. Dovey OM, Bradley A … Vassiliou GS; Blood 2017; 6 DOI: 10.1182/blood‐2017‐01‐760595
Enhancing the genome editing toolbox: genome wide CRISPR arrayed libraries. Metzakopian E, Strong A … Bradley A; Scientific Reports 2017; DOI: 10.1038/s41598‐017‐01766‐5
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11 Allan Allan Gene mutations or environmental factors such as infection or drugs can have genome‐
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h not always clear which of these perturbations can be buffered by the system and which lead to detrimental outcomes as reflected in morphological changes or reduced health. c
i We inve stigate in vivo gene regulatory responses to challenges such as genetic mutations, chromatin disruption and infection. Specifically, we use our zebrafish mutant w archive of ~43,000 alleles covering 60% of protein‐coding genes, CRISPR/Cas9 t tih mutagenesis and genome‐wide sequencing approaches to understand the relationship of chromatin structure, transcriptional changes and phenotypic outcomes. For example, partial loss of gene function can have substantial effects on genome‐wide gene
en expression levels without gross morphological defects. This provides an opportunity to dissect gene regulatory networkks and distinguish network‐specific, but tolerated gene
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The gene regulatory basis of genetic compensation during neurral crest induction. Dooley CM, Wali N … Busch‐Nentwich EM; bioRxiv 2018; doi.org/10.1101/314534
usc Placentation defects are highly prevalent in embryonic lethal mouse mutants. Perez‐Garcia V … Busch‐Nentwicch EM … Hemberger M;
B Bh Nature 2018; doii: 10.1038/nature26002
A high‐resolution mRNA expression time course of embryonic development in zebrafish. White RJ, Collins JE … Busch‐Nentwich; Elife 2017; DOI: 10.7554/eLife.30860
th The age of heterozygous telomerase mutant parents influences the adult phenotype of their e offspring irrespective of geenotype in zebrafish. Scahill CM, Digby Z … Busch‐Nentwich; Wellcome Open Research 2017; DOI: 10.12688/wwellcomeopenres.12530.2 b bth
Loss of the chromatin modifier Kdm2aa causes BrafV600E‐independent sppontaneous melanoma in zebrafish. sa Scahill CM, Digby Z … Busch‐Nenntwich; PLoS Genetics 2017; DOI: 10.1371/journal.pgen.1006959
li li e m [email protected]
E E 12 We are a newly established research group that focuses on the antibody response to rotavirus infection and vaccination.
Protective rotavirus antibodies: Rotavirus is a common cause of gastroenteritis in childrenn, especially in low‐income countries. An estimated 215,000 children under five years olld die from rotavirus infection every year. Fortunately rotavirus vaccines have recently become available, but the exact mechanisms by which these vaccines work are poorly understood. This means that predictinng vaccine efficacy is a challenge.
We elucidate the mechanisms of antibody‐mediated protection to rotaviruus using molecular techniques. In collaboration with clinical partners, this enables the
development of accurate tests to predict rotavirus vaccine effectiveness, and help to develop the next generation of rotavirus vaccines.
Maternal antibodies: Rotavirus vaccines are negatively affected by the presence of maternal antibodies that are transferred from the mother to infant and protect the infant from infection. It is not known how maternal antibodies prevent vaccines from inducing protective immune responses in infants. We are using different models for rotavirus infection, combined with genetic approaches and deep sequencing to unravel the mechanisms of maternal antibody vaccine blockade. It is anticipated that understanding the activity of PUBLICATIONS maternal antibodies will lead to Complement C4 prevents viral infection through rational design of improved nneonatal capsid inactivation. Cell Host Microbe 2019 vaccines.
Caddy Characterization of innate immune viral sensors Caddy in patients following allogeneic hematopoietic
stem cell transplantation. Caddy SL et aal; Innate Immunity 2018; DOI: 10.1177/1753425918757898
Genogroup IV and VI canine noroviruses bind to histo‐blood groups antigens. Caddy S et all; Journal of Virology 2014; DOI: 10.1128/JVI.01008‐14
Norovirus‐Mediated Modification of the Translational Landscape via Virus and Host‐ Induced Cleavage of Translation Initiation Factors. Emmott E … Caddy S … Goodfellow; Molecular Cell Proteomics 2017; DOI: 10.1074/mcp.M116.062448
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13 Sarah Sarah We research humoral immunity in humans, how this goes wrong in disease and how it can be manipulated therapeutically using experimental medicine studies. In collaboration with Glaxo‐Smith‐Kline we recently investigated how belimumab affects the B cell compartment in renal transplannt recipients,. We found it suppressed new antibody formation and skewed residual B cells to an IL10‐producing, regulatory phenotype.
Autoantibodies are associated with a number of kidney diseases, and antibody‐mediated rejection has a negative impact on transplant outcomes. We use human kidney tissue to profile resident immune cells using flow cytometry, mass cytometry, aand RNA sequencing, and complementary mouse models to understand function. We have shown how the intrarenal sodium gradient can influence mononuclear phagocyte position and function to optimise defence against ascending infection.
Although IgA is the dominant antibody isotype found at mucosal suurfaces during health, genetic variation in FcgRs can influence susceptibility to inflammatory bowel disease (IBD), suggesting that IgG may be important during inflammationn. We are currently investigating how the induction of IgG in the gastrointestinal tract can activate gut‐ resident cells, how this is regulated, and whether this is important in IBD.
Increasing evidence shows immune cells change their metabolism in response to activation signals and that some of PUBLICATIONS these changes may be required for
their function. We investigate how IgG Single‐cell transcriptomess from human kidneys reveal the cellular identity of renal tumors. immune complexes affect macrophage Clatworthy Clatworthy Young MD … Clatworthy MR … Behjati S; Science 2018; DOI: metabolism and influence IgG‐ 10.1126/science.aat1699
associated tissue inflammation. PI3Kδ hyper‐activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody‐independent manner. Stark AK … Clatworthy MR … Okkenhaug K; Nature Communications 2018; DOI: 10.1038/s41467‐018‐05674‐8
Belimumab in kidney transsplantation: an experimental medicine, randomised, placebo‐ controlled phase 2 trial. Banham GD, Flint SM … Clatworrthy MR; Lancet 2018; DOI: 10.1016/S0140‐6736(18)30984‐‐X
nna nna Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zonne. Berry MR, Mathews RJ … Clatworthy MR; Cell 2017; DOI: 10.1016/j.cell.2017.07.022
Me Me 14 We use complementary genomics and phenotypic approaches to explore host/pathogen interactiions, and are interested in how pathogens colonise and cross mucosal surfaces and then spread and survive in the deeper tissues of the body. We use the analysis of microbe populations to identify candidate evolutionary signatures that we can then
analyse to determine their contribution to phenotype, if any.
In one aspect of our work we perform clinical studies that enable us to develop mmethods to analyse the pathogen, microbiota and host response simultaneously, and to bring genomics into clinical practice. We have interests in antibiotic resistancce, how pathogens evade therapies, and in vacciness. Our focused research topic for maany years has been typhoid, or enteric fever, and the Salmonella bacteria that cause it.
Our clinical work has enabled clinical teams to track infections by sequencing pathogens as they enter the hospital. We also look at environmental microbial contaminatiion using genomics and informatics approaches, to link specific environmental conteexts with patient isolates. This allows us to monitor antibiotic resistance, with the ambbition of promotiing the appropriate use of antibiotics.
Our work on typhoid has led to the creation of the global whole genome database for Salmonella Typhi which houses over 5,000 isolates from around the world. This database monitors the spread of typhoid and identifies novel antibiotic resistant poppulations. With othher groups we investigate typhoid pathogenesis using microbial geneticcs linked to field studies, and human challenge models using stem cells. The value oof these models lies in our ability to challenge PUBLICATIONS them with pathogens and ccompare Dougan Phylogeographical analysis of the dominant functional readouts to clinical Dougan multidrug‐resistant H58 clade of Salmonella outcomes. Typhi identifies inter‐ and intracontinental transmission events. Wong V, Baker S… Dougan G; Nature Genetics 2015; doi: 10.1038/ng.3281
Identification of enterotoxigenic Escherichia coli (ETEC) clades with long‐term global distribution. von Mentzer A, Connor TR … Dougan G; Nature Genetics 2014; DOI: 10.1038/ng.3145
Emergence of host‐adapted Salmonella enteritidis through rapid evoluton in an immunocompromised host. Klemm E … Dougan G … Kingsley RA; Nature Microbiology 2016; DOI: 10.1038/nmicrobiol.2015.23
Interleukin‐22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells. Forbester JL, Lees EA … Dougan G; Proceedings of the National Academy of Sciences 2018; DOI: 10.1073/pnas.1811866115 g d312@c am.ac.uk
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The metabolic repertoire of immune cells, which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigeenetic programming of metabolic geenes, enables and modulates specific immune functions.
Our goal is to delineate the molecular basis of how cellular metabolism is regulated, and itself regulates, immune‐function in healtth and disease states, and to deffine how environmental cues are integrated at the cellular level by immune cells to shape cellular metabolism and function. Hess Hess
PUBLICATIONS
The spectrum of T cell metabolism in health and disease. Bantug GR, Galluzzi L … Hess C; Nature Reviews Immunology 2018; DOI: 10.1038/nri.2017.99
Mitochondria–ER contact sites are immunometabolic hubs that orchestrate the rapid recalll response of memory CD8+ T cells. Bantug GR, Fischer M … Hess C; Immunity 2018; DOI: 10.1016/j.immuni.2018.02.012
Memory CD8+ T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function. Balmer ML, Ma EH … Hess C; Immunity 2016; DOI: 10.1016/j.immuni.2016.03.016
Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.. Kolev M … Hess C … Kemper C; Immunity 2015; DOI: 10.1016/j.immuni.2015.05.024
Rapid effector function of memory CD8+ T cellss requires an immediate‐early glycolytic switch. Gubser PM, Bantug GR … Hess C; Nature Immunology 2013; DOI: 10.1038/ni.2687
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Disease aassociation of genetic variation may pinpoint pathophysiologic mechaniisms and can give insight into protein function, paarticularly for receptors whose ligands are unknown or controversial. Coding variants often affect pathways of wider biological importance.
The orphan G‐protein coupled receptor Gpr35 is one such gene, where a coding variant has been associated with an increased risk for inflammatory bowel disease, andd primary sclerosing cholangitis that has an increased cancer risk. We investigate GPR35’s ffunction, and in particular the communication of immune cells expressing this receptor and their environment.
We are also interested in GPR35’s molecular interactions with other cell membrane proteins and its implications on signalling events and cell function.
PUBLICATIONS
GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump. Schneditz G, Elias JE … Kaneider NC; Science Signaling 2019; DOI: 10.1126/scisignal.aau9048
Reversal of murine alcoholic steatohepatitis by Kaneider pepducin‐based functional blockade of Kaneider interleukin‐8 receptors. Wieser V, Adolph TE; Gut 2017; DOI: 10.1136/gutjnl‐2015‐310344
A matrix metalloprotease‐PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. Tressel SL, Kaneider NC; EMBO Molecular Medicine 2011; DOI: 10.1002/emmm.201100145
'Role reversal' for the receptor PAR1 in sepsis‐ induced vascular damage. Kaneider N et al; Nature Immunology 2007; DOI: 10.1038/ni1525
Reversing ssystemic inflammatory response syndrome with chemokine receptor pepducinss. Kaneider N et al; Nature Medicine 2005; DOI: 10.1038/nm1245
n k 428@c am.ac. uk
19 15 Nicole
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Genetic studies have successfully identified many regions of the human genome that alter an individual’s risk of autoimmune or inflammatory disease, but the molecular mechaniisms that underpin these associatioons – and hence the reason they increase disease susceptibility – remain largely unknown.
We uncover the biology responsible for genetic associations in immune‐mediated disease by combining genetics, genomics, molecular biology, and immunologgy‐based approaches. We have a particular focus on the non‐coding genome, including ennhancers and non‐coding RNA, and the role that theyy might play in regulating immune responses. Our goal is to not only shed new light on pathways involved in disease pathogenesis, but to also provide novel therapeutic opportunities. Other interests include better understanding the genetic and biological ddeterminants of prognosis in autoimmune, inflammatory and infectious diseases ‐ as distinct from those pathways that drive disease development.
James currently holds a Wellcome Trust Intermediate Clinical Fellowship, and has
recently spent 2 years at Harvard as PUBLIC ATIONS part of this. He is also a member of
Genome ‐wide association study identifies the UK and International IBD Genetics distinct genetic contributions to prognosis and Consortia. susceptibillity in Crohn's disease. Lee JC et al; Nature Genetics 2017; DOI: 10.1038/ng.3755
Genome‐wide association study implicates immune activation of multiple integrin genes in inflammatoory bowel disease. Lee de Lange KMM … Lee JC … Barrett JC; Nature Genetics 2017; Lee DOI: 10.1038/ng.3760
Genome‐wide association studies in Crohn's disease: past, present and future. Verstockt B, SSmith KG & Lee JC; Clinical &Translational Immunology 2018; DOI: 10.1002/cti2.1001
Human SNP links differential outcomes in inflammatoory and infectious disease to a FOXO3‐regulated pathway. Lee JC et al; Cell 2013; DOI: 10.1016/j.cell.2013.08.034
Gene‐expression profiling of CD8 T‐cells predicts prognosis iin patients with Crohn disease and ulcerative colitis. Lee JC et al; Journal of Clinical Investigation 2011; DOI: 10.1172/JCI59255
21 18 James
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Vaccines are one of the most powerful tools to prevent infectious diseases. New vaccine s are currently planned or already in the development pipeline. Epidemiological and clinical studies are necessary to determine the burden of existing diseases, the level of vaccine protection and identification of target populations. They can improve
existing vaccination schemes and quantify the add‐on benefits such as herd protection and vaccine effects pertinent to the reduction of antimicrobial resistance.
Jointly with the International Vaccine Institute in Seoul, Republic of Korea, and other
institutions, we operate field sites in 14 African and 12 Asian countries capable of conducting multi‐center epidemiological field studies that provide well‐characterized sampless for basic research and as a platform for the conduct of clinical trials.
Our research focuses on late‐stage support of generating clinical data for a novel typhoid conjugate vaccine through a cluster‐randomized Phase III trial in Ghanaa and an effectiveness trial in the Democratic Republic of the Congo, thereby generatinng data urgently required by the World PUBLIC ATIONS Health Organization and Gavi, the What is the best immunization strategy for Vaccine Alliance. protecting African children against invasive Salmonella disease? Jeon HJ, Pak GD … Marks F; Clinical Infectious Diseases This well‐established field network 2018; DOI: 10.1093/cid/ciy386 can be leveraged as a platform for scientists in CITIID and beyond to Updates estimates of typhoid burden in sub‐ Marks Marks Saharan Africa. add‐on study activities and obtain Kim J‐H, Mogasale V … Marks F; Lancet Global Health 2017; samples in high quality to execute
DOI: 10.1016/S2214‐109X(17)30328‐5 basic sciences research.
Incidence of invasive Salmonella disease in sub‐ Saharan Africa: a multicenter population‐based surveillance study. Marks F et al; Lancet Global Health 2017; DOI: 10.1016/S2214‐109X(17)30022‐0
Effectiveness of the Viet Nam produced, mouse brain‐derived, inactivated Japanese encephalittis vaccine in Northern Viet Nam. Marks F et al; PLoS Neglected Tropical Diseases 2012; DOI: 10.1371/journal.pntd.0001952
Sm‐p80‐based schistosomiasis vaccine: double‐ blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission‐blocking efficacy. Zhang W … Marks F … Siddiqui AA; Annals of the New York Academy of Science 2018; DOI: 10.1111/nnyas.13942 fm471@ca m.ac.u k 23 Florian Florian
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The immune response is a powerful and complex system that has evolved to protect us from pathogens and from tumours. Loosing control of that system results in immunopathology, manifest in a broad rangge of diseases including autoimmunity (such as T1D, lupus, multiple sclerosis), autoinflammmatory disease (such as Crohn’s disease,
Ulcerative colitis), infection and malignancy.
We use a systems immunology approach – modelling a broad range of quantitative traits as a me ans of discovering previously unsuspected relationships between them – to better understand the dysfunctional immune response in human disease. Our goal is to better understand what shapes an aberrant response and to use the information to indicate novel tests and/or interventions to help clinicians treating immune pathology.
Examples of the approach include, 1) the association of T‐cell exhaustion withh clinical outcome in numerous autoinflammatory/autoimmune diseases, 2) the use of this observation to develop a clinical assay for patient stratification, being brought to the clinic through a University start‐up (PredictImmune), 3) the identification of a natural killer cell subset associated with clinical outcome in multiple sclerosis, and 4) the identification of molecular signatures predicting clinical onset of T1D in at risk chiildren.
Ongoing projects include predicting and understanding clinical progression at various stages in T1D (in collaboration with the TEDDDY consortium, TrialNet and JDRF), multiple sclerosis (in collabo ration with the Immune Tolerance Network), and in human ageing (in collab oration with the SardiNIA consortium) in addition to a Wellcome‐funded study investigating novel ways of PUBLICATIONS modulating T cell exhaustion. Metabolic exhaustion in cancer, infection and autoimmunity. McKinney EFF & Smith KGC; Nature Immunology 2018. DOI: 10.1038/s41590‐018‐0045‐y
T cell exhaustion and immune‐mediated disease – the potential for therapeutic exhaustion. McKinney McKinney McKinney EFF & Smith KG; Current Opinion in Immunology 2016; DOI: 10.1016/j.coi.2016.09.005
T cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. McKinney EFF & Smith KG; Immunology & Cell Biology 20116; DOI: 10.1038/icb.2016.81
T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection. McKinney EFF, Lee JC … Smith KG; Nature 2015; DOI: 10.10388/nature14468 [email protected] 25 Eoin Eoin
Yorgo Modis functio cells respons non Our health level resoluti set it underst silencin sensing cell’s genomi must Viruses
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We use advanced bacterial genomics and metagenomics to better understand the evolution and spread of pathogens locallly, nationally and globally. Realising the complexity of big data and its limited understanding in most developiing and underdeveloped countries, we mine genomic data for robust, risk‐informative diagnostic markers. I use these markers and design smart detection probes as field‐compatible technoloogies. This technology‐driven global health approach makes my research accessible to the communities who need it most.
PUBLICATIONS
Defining endemic cholera at three levels of spatiotemporal resolution within Bangladesh. Domman D … Mutreja A … Thomson NR; Nature Genetics Mutreja 2018; DOI: 10.1038/s41588‐018‐0150‐8 Mutreja
Integrated view of Vibrio cholerae in the Americas. Domman D … Mutreja A … Thomson NR; Science 2017; DOI: 10.1126/science.aao2136
Genomic history of the seventh pandemic of cholera in Africa. Weill FX … Mutreja A … Thomson NR; Science 2017; DOI: 10.1126/science.aad5901
Retrospective Analysis of Serotype Switching of Vibrio cholerae O1 in a Cholera Endemic Region Shows It Is a Non‐random Process. Karlsson SL … Mutreja A … Lebens M; PLoS Neglected Tropical Diseases 2016; DOI: 10.1371/journal.pntd.0005044
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The human gastrointestinal tract houses a large number of microbes, collectively known as the microbiota that supports host metabolism, immune development and pathogen resistancce. Intestinal dysbiosis, disruption oof bacterial diversity in the gut, can result from antibiotic use or pathogenic infection and has been strongly linked to increased disease susceptibility. This dysbiosis‐induced susceptibility indicates that normal commensal bacteria are capable of preventing disease; however, mechanisms involved in key host‐commensal interactions are still largely unknown.
We seek mechanistic insights into the influence of commensal microbes oon both intestinal infections and inflammation and systemic immune responsess. These fundamental insights will give us a bettter understanding of infectious diseases, autoimmune disorders and even cancer, and will enable the development of new approaches to combat these diseases. Using in vivo models, cellular immuunology, transcriptomics and proteomics and working closely with the Wellcome Trust Sanger Institute, we characterise the complex inteeractions between the commensal microbial community, intestinal epithelium and adaptive immune cells. Pedicord Pedicord PUBLICATIONS
Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Hoytema van Konijnenburg DP … Pedicord VA … Mucida DD; Cell 2017; DOI: 10.1016/j.cell.2017.08.046
Exploiting a host‐commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Pedicord VA et al; Science Immunology 2016; DOI: 10.1126/sciimmunol.aai7732
A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Rangan KJ, Peedicord VA … Hang HC; Science 2016; DOI: 10.1126/science.aaf3552
Absence of MHC class II on cDCs results in microbial‐dependent intestinal inflammation. Loschko J … Pedicord VA … Nussenzweig MC; Journal of Experimental Medicine 2016; DOI: 10.1084/jem.20160062
[email protected] am.ac. uk
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Human cytomegalo virus (HCMV), the largest known human herpesvirus, is a major cause of disease in individuals whose immune systems are compromised or immaturee and is the
commonest infective cause of congenital damage to the central nervous systemm. Similarly,
it can also be life‐threatening in the context of organ or bone marrow trannsplant or advanced HIV infection.
Unlike many other viruses, HCMV is never cleared after primary infection but persists for the lifetime of the host. In part, this is due to the profound ability of HCMV to avoid the host’s immune response.
However, this lifelong viral persistence is allso underpinned by a biological property of all
herpesviruses; the ability to undergo latent infection where viral genomes are carried
silently in the absence of detection of infectious virions. It is now clear that that
reactivation of virus from these latent poolls is also a major cause of congenital infection
as well as causing much of the HCMV‐mediated disease obsserved in
immunocompromised transplant patients and patients with AIDS.
We seek the molecular basis of viral latency and reactivation of this persisteent human virus and how the host immune response combats virus disease. Such an understanding of how latent virus infection alters cellular functions to optimise the cell for latent carriage allows us to identify potential PUBLICATIONS “Achilles heels” of the virus to enable Defining the transcriptional landscape during us to target the latent viral reservoir in Cytomegalovirus latency with single‐cell RNA Sequencing. patient populations. Shnayder M, Nachshon A … Stern‐Ginossar N; MBio 2018; DOI: 10.11288/mBio.00013‐18
DeSUMOylase activity is required for Sinclair Cytomegalovirus reactivation from latency. Sinclair
Poole EL, Kew VG … Reeves MB; Cell Reports 2018; DOI: 10.10166/j.celrep.2018.06.048
Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein. Krishna BA, Spiess K … Sinclair. Nature Communications 2017; DOI: 10.10388/ncomms14321
Latency‐Associated Expression of Human Cytomegalovirus US28 attenuates cell signaling pathways to maintain latent infection. Krishna BA, Poole E … Sinclair JH; MBio 2017; DOI: 10.11288/mBio.01754‐17
31 John John Ken Smith kg M 1 T fl H D M o T 1 L s g G D M a M P e e u a u a 0 0 0 0 e e u u
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Synthetic biology seeks to engineer biological processes. “Xenobiology” goes further by manipulating biological processes using artiificial chemistries. For example, fuunctional oligos have huge potential for precision mediccine as they can be made to target tumours or pathoggens with remarkable specificity, and are easily prepared on a standard desktop oligo synthesiser.
Unfortunately, natural processes present some serious hurdles: nucleases severrely limit their stability in vivo, and their chemical unifformity impacts the type of interactions or mechanisms they can participate in. Taking lessons learnt from the medicinal chemistry of antisense therapeutics, artificial oligo chemistries – or “xeno nucleic acids” (XNAs) ‐ offer properties beyond those of DNA and RNA, such as reduced immunogenicity and nuclease‐ resistance in serum.
We have established methods to evolve biostable XNAs into high affinity aptamers for specific targets, into a variety of catalysts or “XNAzymes”, and self‐assembling nanoscale polyhedra. We are exploring the developpment of functional XNAs as a platform technology to direct or manipulate biologgy, for example using assemblies of XNA aptamers to target pathogens and tumor cells precisely modulate immune effector mechanisms in response to disease. XNAs hhave the potential to offer the molecular precision and function of bbiologics PUBLICATIONS but the advantages of short oligos, A synthetic genetic polymer with an uncharged including the ability to turn backbone cchemistry based on alkyl‐phosphonate nucleic acids. activities on & offf with Arangundy‐Franklin S … Taylor AI … Holliger P; Nature complementary strands as Chemistry 2019 antidotes. Beyond DNA and RNA: the expanding toolbox of synthetic genetics , RNA Worlds. Taylor AI, Hooulihan G. and Holliger P; 2019; CSH Press
Taylor Nanostructures from synthetic genetic polymers. Taylor Mutschler H,, Taylor AI, … Holliger P; ChemBioChem 2016;
DOI: 10.7554/eLife.43022
Catalysts from synthetic genetic polymers. Taylor AI, Pinheiro VB … Holliger P; Nature 2015; DOI: 10.1038/nature13982
Synthetic genetic polymers capable of heredity and evolution. Pinheiro VB, Taylor AI … Holliger P; Science 2012; DOI: 10.1126/science.1217622
33 Alex Alex We elucidate the aetiology of human immune‐mediated diseases, to improve diagnosis
and treatment. We use integrative statistical analysis of genomic data and develop statistical methods to improve inference, or adapt to new biological teechniques: Genetic association discovery and fine mapping. This focuses on increasing power through optimal study design, borrowing information between related diseases using the conditional False Discovery Rate, and distinguishing the variant(s) driving the association from their correlated neighbours. Comparative genetic studies of immune‐mediated diseases. We usse co‐localisation to
integrate over the fine mapped posterior distributions of causal variants of different diseases to determine which diseases share which genetic risk factors Integrative analysis of genetic and omic data. Co‐localisation methods to enable us to understand disease mechanisms by mapping disease associated genetic variants to the genes they regulate. We also develop techniques to integrate genetic association data with maps of promoter‐enhancer chromatin contacts in the cell nucleeus. Dissection of heterogeneity within diseases. Human diseases have been classified according to clinical presentation, but there is increasing evidence that clinical symptoms
may not align to aetiological causse. PUBLICATIONS This is motivating a transition towards Chromosome contacts in activated T cells identify alternative aetiological, molecular, or autoimmune disease candiidate genes. treatment‐responsive, classifications Burren OS, Rubio García A … Walllace C; Genome Biology 2017; DOI: 10.1186/s13059‐017‐‐1285‐0 of diseases and their subtypes. Our comparative studies of diseases can A method for identifying genetic heterogeneity within phenotypically‐defined disease subgroups. inform treatment decisions using Liley J, Todd JA & Wallace C; Natture Genetics 2017; DOI: 10.1038/ng.3751 stratified medicine approaches. A pleiotropy‐informed Bayyesian false discovery Wallace Wallace rate adapted to a shared coontrol design finds new disease associations from GWAS summary
statistics. Liley J & Wallace C; PLoS Genetics 2015; DOI: 10.1371/journal.pgen.100449926
Lineage‐specific genome arrchitecture links disease variants to target genes. Javierre BM … Wallace C … Fraser P; Cell 2016; DOI: 10.1016/j.cell.2016.09.037
Statistical colocalization off genetic risk variants for related autoimmune diseasses in the context of common controls. Fortune MD, Guo H … Wallace C;; Nature Genetics 2015; DOI: 10.1038/ng.3330 cew 54@ca m.ac.uuk
Chris Chris 34 Infection by human cytomegalovirus (HCMV) of immunocompetent indiviiduals is generally asymptomatic or mild, and is self‐limiting. However, HCMV is never cleared after primary infection, but persists for the lifetime of the host as a latent infecttion that avoids immune surveillance. While HCMV is a paradigm for viral immune evasion strategies, the resolution of primary infection is dependent on effective CD4 and CD8+ T cell ressponses. In contrast, infection of individuals whose immune systems are compromised (such as HIV/AIDS patients and transplant patients) or immature (such as a foetus) often leads to wide spread viral replication and dissemination and this can often be life threatening. Similarly, reactivvation of the virus in individuals wwho are immunosuppressed also leads to significant morbidity and mortality.
We address a number of important questions concerning the immunobiology of HCMV both in lytic and during latent infection, with a particular focus on the generation, maintenance and function of memory CD4+ and CD8+ T cells and the immune evasion
mechanism employed by the virus to modulate Natural Killer cell function. We eestablish how this human pathogen persists for the liifetime of the host in the presence of a fully competent and potent cell mediated immune response. Our view is that this knnowledge PUBLIC ATIONS will allow us to develop credible strategies to make latently infected HCMV Specific CD4+ T Cells are poly‐functional and can respond to HCMV Infected Dendritic cells immunological targets and Cells in vitro. thus lead to the elimination of Jackson SE, Sedikides GX … Wills MR; Journal of Virology 2017; DOI: 10.1128/JVI.02128‐16 latent HCMV reservoirs in vivo and
in solid organ donor tissue, which Diverse speecificities, phenotypes, and antiviral activities of cytomegalovirus‐specific CD8+ T would have a significantt clinical cells. Jackson SE, Sedikides GX … Wills MR; Journal of Virology benefit for transplant patients. Wills 2014; DOI: 10.1128/JVI.01477‐14 Wills
Human cytomegalovirus latency‐associated proteins elicit immune‐suppressive IL‐10 producing CD4+ T cells. Mason GM, Jackson … Wills MR; Plos Pathogens 2013; DOI: 10.1371/journal.ppat.1003635
Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T‐cell migration and suppression of effector function. Mason GM, Wills M … Sinclair JH; Proceedings of the National Academy of Sciences 2017; DOI: 10.1073/pnas.1204836109 mrw1 [email protected]
35 Mark Mark IMPACT From genetic analysis to personaliised medicine in IBD
Professor Ken Smith
One in every three‐hundred people has inflammatory bowel disease (IBD, comprising Crohn’s disease & ulcerative colitis) in the developed world and its incidence is rising fast in developing countries. In the UK alone there are around 620,000 sufferers with an annual cost to the NHS in excess of £1bn. Around half of patients have an aggressive, relapsing disease course, while in others the disease is more quiescent.
Unfortunately, prognostic markers that can rreliably identify these patients are not available in clinical practice. This hinders disease management because patients with aggressive disease will be undertreated by conventional escalating dose therapy, while those with quiescent disease can be exposed to the risks and side‐effects of unnecessary immunosuppression.
Research in the Professor Smith’s lab found a transcriptional signature that is detectable within peripheral blood CD8 T‐cells (a type of white blood cell) at diagnosis and which correlates with long term clinical outcome in IBD. The signature reflects a process called exhaustion, in which T‐cells progressively lose the ability to sustain an effective immune response. Paatients following an aggressive disease course have less exhaustion than those with a quiescent course. However, translating these findings to the clinic originally presented a technical challenge as blood cell populations needed separating to see a signal, something that is not practical in a routine clinical setting. To meet this challenge the researchers utilised novel approaches too find a whole blood biomarker that could provide the same results without the need for cell separatiion.
The answer was to measure gene expressioon using microarrays and then use machine learning to identify the suitable whole‐blood biomarker. Ultimately this led to the identiffication of a 15 gene assay that could identify different disease courses by stratifying patients into aggressive and quiescent types of IBD, and an independent, prospective multicentre study validaated these findings.
Having established these principles, a spin‐out company (PredictImmune Ltd) wwas created through Cambridge Enterprise to translate this work into the clinic. The prognostic tests it provides for immune‐mediated conditions can aid disease management and improve patient outcomes. As differing IBD patients may require different treatment regimens, the test ensuures that they receive the most appropriate course of treatment and avoid excessive side effects resulting from over‐ treating the quiescent group, or excessive morbidity from under‐treating the aggressive group. With funding from the Wellcome Trust, Predictimmune is also running a biomarker‐stratified trial that is a first of its kind for inflammatory disease and will determine whether the biiomarker can deliver personalised care.
The test uses a small blood sample to accurately predict each patients’ outccome at the point of diagnosis, and is available as a laboratory testing service and soon also as a kit. The group is also developing predictive tests for other immune‐mediated diseases that pose long‐term burdens on patients as well as imposing a financial burden society. They include tests for lupus, multiple sclerosis, diabetes mellitus and rheumatoid aarthritis.
36 PATH WAY ANALYSIS I M PLICATE S REGUL ATION O F IMMUN E RESPO NSES
AND MONON UCLEAR PHAGOCYTES IN CROHN’S DISEASE PROGNO SIS
(a) Horizontal bar plot of –log10 (P values) for the top 40 most enriched pathwaays in an analysis of 29 LD‐pruned prognosis‐associated SNPs (meta P < 1 x 10‐5) across 1,751 pathways annotated by Gene Ontology. (b) Bar plot of –log10 (P values) for 155 specific cell‐types and conditions. Significant enrichment was observed in “monocyte‐derived macrophages stimulated by M‐CSF” and “monocyte‐derived macrophages stimulated by M‐CSF and interferon‐gamma”. Other non‐
immune cell‐types included neural, skin, lung, liver, stem cells, smooth muscle,, stromal cells, bone marrow progenitors, endothelial and epithelial cells. Dotted lines represent Bonferroni‐corrected significance thresholds. Analyses performed using SNPsea.
S EE THE WORK HERE
d oi.org/10.1186/ISRCTN118 08228 h ttps://www.p redictimmune.com/ 37 IMPACT New trreatments for Tuberculosis
Professor Ramakrishnan
Tuberculosis (TB) is an infectious disease thhat affects over 10 million people worldwide, of whom 10% die if the disease is untreated. Globally it is one of the top 10 diseases that causes death, and over 95% of these deaths occur in low and middle‐income countries. Ending the TB epidemic by 2030 is one of the health targets of the United Nations Sustainable Development Goals, but multidrug‐ resistant TB (MDR‐TB) is a continuing public health crisis and a health security thhreat.
Eradication of TB is impeded by the need for long complex treatment ‐ six months with four drugs ‐ for duraable cure. Furthermore, this need for long treatment could be the catalyst for the development of antibiotic‐tolerant TB. Reseearchers in Professor Ramakrishnan’s lab have found that the actively‐growing bacteria become antibiotic‐tolerant upon entry into host macrophages (part of our immune system, and the bacteria’s site of growth) by inducing bacterial effflux pumps. With this knowledge, the researchers are testing the therapeutic value of a several drugs that are known to inhibit these efflux pumps and are already approved for other purposes. For example, a clinical trial with verapamil (commonly used as an antiarrhythmic) as a treatment‐shortenning agent has been approved and funded by the Government of India and is entering Phase 2. Linked to this trial, studies to better understand bacterial efflux pump‐mediated drug tolerance mechanisms are in progress through a multi‐investigator collaborative grant from the British MRC and the Inndian Department of Biotechnology.
Other clinical trials are also underway for studies on meningitis TB, the most severe and lethal form of this disease. In this study, Professor Ramakrishnan and her colleagues found that TB susceptibility is heightened in conditions of inadequate or excessive inflammation, and is regulated by the balanced production of steroid called eicosanoids. The balance of these steroids is maintained by an enzyme that is referred to as leukotriene A4 hydrolase (LTA4H), and it is variantts of this enzyme that control the severity of TB meningitis. In collaboration with colleagues from thhe Oxford University Wellcome Trust Research Unit (OUCRU) in Vietnam, researchers from the Rammakrishnan lab have found that because of this variation in the enzyme, the standard therapy for meningitis TB is only effective in patients with a high inflammatory state, while patients with the low inflammatory state patients may be harmed by it.
Based on this finding, the OUCRU investigators have begun a randomised clinicaal trial where patients are genotyped and those with the low‐LTA4H genotype are given steroid treatment or placebo. If the previous findings are confirmed, then in the future steroid treatment will be restricted to the excessive inflammation subset, improving the outcome of both groups. To address this, in the meantime, the zebrafish is being used to reveal mechanistic details of the LTA4H‐mediated low and high inflammatory states. New targets for trreatments are being revealed and drugs that have already been approved for other purposes have been identified. The use of personaliseed genomics will have consequences for guiding clinical treatmentts, where patients from the two LTA44H genotypes will be treated with different therapies.
ag97 [email protected] .ac.uk
38
C E REBROSPINAL FLUID (CSF) LEVELS OF CYTO KINE EXPPRESSION IN
H UMAN I M MUNODEFICIENCY VIRUS (HIV)–INFECTED (( I) AND H IV‐ UNINFEC TED (UI) PATIENTTS WITH TUBERCU LOUS M EENINGITIS
Concentrations are in picograms/milliliter for all cytokines except interleukiin 6 (IL‐6), for which
concentrations are in nanograms/milliliteer. Statistical comparisons between HIV‐infected and HIV‐ uninfected were made by the Mann–Whitney test corrected for multiple testing across the 10 cytokines. Only P values of ≤ .05 are shown. Abbreviations: IFN‐γ, interferon γ; TNF‐α, tumor necrosis factor α.
SEE THE F ULL A R TICLE AT
DOI: 10.10 93/infdis/jix050
39 IMPACT The immunity of inflammatory bowwel disease is exposed
Professor Arthur Kaser
The incidence of Inflammatory Bowel Disease (IBD) is doubling every ten years. The increase in the number of children diagnosed with the dissease is of particular concern. Resiistance to drugs and patients who do not respond to treatment is also a challenge.
However, the picture is not all bad. While there was no available treatment 30 years ago, now at least, thhere are several therapeutic interventions that can be used. For example, anti‐TNF treatment transformed the lives of many following its approval in 1998, and antibodies against integrin and interleukin‐23 have been more recently been employed.
Studies by Professor Kaser’s lab, have been partly responsible for some of these successes. These have enabled the development of experimental methods for examining the ennvironmental stresses and microbes that could be responsible for triggering IBD. Simultaneously they have probed the genetics that are associated with the disease. They have found that of the over‐‐200 genetic loci that are associated with IBD, variations in one protein particularly stand out. Proofessor Kaser and his researchers have used state‐of‐the‐art methods to study it.
Unusually, the protein they identified was of unknown function and lacked any similarity to other known proteins. This in itself was unusuaal, yet it was also associated with an increased risk of juvenile idiopathic arthritis and leprosy. At the time the link between these diifferent diseases was striking, but slowly over the last two years a number of other genetic changes have been identified that unite them, something that suggests a common cause.
The scientists named the unknown protein FAMIN, a term that is short for Fattty Acid Metabolism– Immunity Nexus. This name reflected their finding that FAMIN was highly expressed in macrophages, where it interacts with fatty acid sysnthase and is involved in the metabolism of cellular lipids. A change in FAMIN had a negative impact oon the energy stores of these essential immune cells. Consequently, macrophages that contained mutations in FAMIN were less able tto kill bacteria. What is more, these effects were seen in the cells of mice and humans, a consistenccy across species that provided welcoming confirmation of the causal genetic risk to IBD.
Metabolic pathways in immune cells are eemerging as important determinants of immunological function and the work of Professor Kaser and his colleagues’ shows that a core metabolic regulator of immune cell function is affected by genetic variation that results in a predisposition to inflammatory diseases and infection. Such findings have profound implications for the treatment of IBD and pave the way for further studies of gene‐environmental interactions. Cambridge has consequently been the epicentre for clinical trials which are ongoing throughout the UK. Importantly, the studies have been accelerated by the unique collaborative environment that is provided by Cambridge, involving researchers in other University departments, as well as other Cambridge centres such as the Wellcome Sanger Institute.
40 FAMIN: A CAU SAL GENETIC RISK FOR INFLAMMATORY BOWEL DISE ASE
(a) Immunoblot analysis (IB) of FAMIN and FASN (right margin) in primary human macrophages
(MΦ) derived from peripheral blood mononuclear cells and in U937 and THP‐1 macrophages
differentiated with PMA (below blots), asssessed after immunoprecipitation (IP) with antibody to FAMIN (anti‐FAMIN), mouse immunoglobulin G (IgG; control) or anti‐FASN (above lanes) or without immunoprecipitation (Input; far riight). Left margin; molecular size, in kilodaltons (kDa). (b) PLA of FAMIN and FASN (yellow) in THP‐1 macroph ages also stained with the DNA‐binding dye DAPI (blue throughout). (c) Immunoblot analysis of FAMIN or GAPDH (loading coontrol) in lysates of HEK293 cells transfected to express humann FAMIN(p.2 54I) or FAMIN(p.254V) or with vector alone
(above lanes), assessed with (top blot) or without (bottom two blots) immunooprecipitation with
anti‐FAASN. (d) Immunofluorescence analysis of the co‐localization of FAMIN (red) with PMP70 (green) in primary human macrophages (enlarged from areas outlined in Supplementary Fig. 2a); far right, enlargement of the area outlined at left. (e) PLA of FAMIN and PMMP70 (red) in THP‐1 macrophages. (f) Immunofluorescence analysis of the co‐localization of FASN (red) with catalase (green) in mFamin+/+ and mFamin−/− M1 macrophag es (M1Φ) and M2 macrophages (M2Φ). (g)
Quantification of the results in f. (h) PLA of FASN and catalase (yellow) iin mFamin+/+ and
mFamin−/− M1 and M2 macrophages. (i) Quan fica on of the results in h. Scale bars (b,d–f,h), 5
μm. Data are representative of three independent experiments (a–e) or one experiment with three mice and six cells (f,g) or ten cells (h,i) imaged per sample (f–i; mean + s.e.m.).
SEE THE F ULL A R TICLE AT
D OI: 10.1038/ni.3532
41 IMPACT Improving sanitation in rural Africa
Dr Ankur Mutreja
Changes in behaviour can provide some of the most successful means of reducing the spread of disease.
In Ghana and Uganda there are often no esstablished infrastructures for sanitatiion and it is common for rural communities to relieve themselves in the open environment. Researchers in Dr Mutreja’s lab are providing evidence that the use of pit‐latrines can improve the health off these communities. They are taking samples from pit‐latrines and individuals within the communities, to provide evidence that pathogen burdens are decreased by following simple sanitation measures. The researchers later return to the communities to explain their findings and coordinate efforts with local community leaders and government officials to promote sanitation and reduce the spread of disease.
In one arm of these studies, samples are taken from the faeces of volunteers, and from pit‐latrines within village communities. By using whole genome sequencing (WGS) off these samples our researchers can examine their genetic components, to establish a highly detailed portrait of the pathogens contained within them, and to probe mechanisms of disease transmission.
Pit‐latrines are a low‐cost solution for reducing disease transmission and require minimal design and materials. By examining their microbial composition our researchers can determine whether the environment of the latrines kills harmful pathogens and limits the spread of disease. By collecting samples from different regions of the pit‐latrines, our teams can also establish the optimal depth at which they should be dug and provide communities and local authorities with practical advice.
In a second arm of these studies the Mutreeja lab trains local community healtth workers to create culturally sensitive digital media that that promotes WASH (clean Water, Sannitation and Hygiene) interventions. This enables these workers to share content with their commmunities using mobile communication platforms such as tablets and mobile phones. This approach provides a flexible solution that can incorporate new knowledge, beliefs and practices, and rapidly communicate these to local communities.
To enable this work, the researchers received an Impact Acceleration Award from the Economic and Social Research Council to foster relations between civil society, academia, NGOs and policy makers. Using a participatory approach they have joined with the community as equal partners, and have used sciientific evidence to promote the use of WASH in areas of Africa wheere clean water and sewage systems are absent. Taking this approach means their research is more responsive to community needs, overcomes many of the cultural barriers that exist within the communities, and engages stakeholders at both local and national levels.
am87 [email protected]
42 SANITA TION IN LOW AND MIDDLE INCOME COUNTRIES
S EE THE WORK HERE
DOI: 10.1 080/17 441692.2018.1536156 43 IMPACT Cholera: a global challenge
Professor Dougan
Infections are caused when disease‐causing agents enter the body and multiply. Cholera is one of these, for which it was estimated that globally there were 1.3 – 4 million cases in 2017 that resulted in 143,000 deaths. This is the consequence of the seventh cholera pandemic that originated in South Asia in 1961 and spread throughout the globe over the course of the next 50 years. Such information can help to determine the factors that are important in the spread of a disease and allows us to gauge the impact of future interventions. Hoowever, little was known about its propagation routes in Africa, the country most affected by this pandemic.
Global‐health researchers in Professor Dougan’s lab have reconstructed the spread of cholera across the African continent by analysing the genomes of 1070 cholera isolates. By mapping this data onto historical records of cholera outbreaks they found that resurgence of cholera in the 1970’s was the result of two strains, one in West Africa, and another in East Africa. The Wesst African strain first appeared between July and September 1970 and was likely to have come fromm Asia. Countries such as Angola saw infection despite being over 1000 km from the closest country with cholera at the time and this then led to an outbreak in Mozambique in 1973. Subsequent reintroductions led to new outbreaks extending over many years up to 2003. The East African strain also appeared in 1970, but was more closely related to strains from the Middle East, suggesting that it may have distinct origins. This strain was associated with several outbreaks over the next 40 yearrs, leading to 125,000 cases of cholera in South Africa in 2001‐2002, and 98,000 cases in Zimbaabwe in 2008‐2009. Originally, even these strains had originated in Asia, but some had circulated in the then endemic Middle East before moving into the East African region. Many of the outbreaks could be linked to large migrations resulting from war or from religious practices such as pilgrimage.
This work has also provided information about antibiotic resistance. Professor Dougan and his colleagues found that African isolates became increasingly resistant over time, and while the earliest of these were recovered in the early 1980’s, only resistant forms have been collected since 2000. This finding reveals that the spread of resistance is likely to have occurred by determinants that were already in these disease‐causing organisms as they spread, rather than independent local acquisitions of resistance. In other words, the bacteria already contained thee genetic information they needed to overcome antibiotics and its emergence was likely to have reesulted from human interventions such as the poorly coordinated use of antibiotics.
These high‐resolution genomic studies show how it is possible to use modern sscientific methods to monitor the spread of diseases, even long after outbreak events. The genomic ddata were consistent with events that were controlled by human activities, and demonstrated that human transmission chains are more important than climatic or environmental speculations. As such, these studies highlight that the long‐term spread and maintenance of cholera in Africa is largeely a consequence of direct, human to human transfer, or indirect infection by water polluted with human faeces. Such large‐scale scientific interpretations over long time scales have an enormous impact on our ability to govern the continued spread of this disease and anticipate future outbreaks.
gd312@cam .ac.uk 44 PHYLO GENY O F THE SEV ENTH P A NDEMIC V. CHOLERAE EL TTOR ISOL ATES
Maximum likelihood phylogeny of the
1070 genomes studied, including M66 as an outgroup. Branches are color‐ coded according to their geographic location, inferred by stochastic mapping of the geographic origin of each isolate onto the tree. (B)
Maximum clade credibility tree for a subset of 228 representative isolates. Twelve introduction events (T) are shown, along with three previously described waves (3) as coloured arrows.
Inferred propagation routes of the seventh pandemic V. cholera, showing twelve introduction events (T) with median date ranges for the most reccent common ancestor in
years. The first numbber indicates the median
MRCA of the African iisolates and their closest relative from the source location, and the second number indicattes the median MRCA of the African isolates. Introductions and inferred secondary transmission chains are indicated by thick and dashed arrows, respectively. Secondary transmissioon chains for West Africa in 1970 to 1971 are bassed on published records. The geographic presence of the various lineages
is indicated by a circle, triangle, and diamond for waves 1, 2, and 3, respectively, and coloured according to the inferred transmission events. The size of the shapes is proportional to the number of genomes analysed.
SEE THE F ULL A R TICLE AT
DOI: 10.1126/scien ce.aad 5901 45 NIH R Cam bridg e BRC P hen otypi ng H u b
CITIID also offers a range of scientific services. The NIHR Cambridge BRC Cell Phenotyping Hub provides state‐of‐the‐art flow cytometry, cell sorting and single‐cell technology facilities for the handling of unscreened human samples. It was established in 2011, to service the immunology community’s need foor human cell sorting and flow phenotyping. In 2012, 700 hours of cell‐sorting time was used. By 2018 this had increased to 3300 hours. This platform provides rapid access flow services to both fundamental and patient‐‐based research from 8.00am ‐ 11.00pm. In future the hub will incorporate a broader range of immunophenotyping and immunoometabolic analysis, coupled to a strreamlined process for analysing vaccine responses (to exxperimental or standard vaccination),, immunomodulatory and immunosuppressive clinical trials and studies that use geneticallly‐defined individuals recruited from the Cambridge BioResource.
The Hub offers a wide range of flow‐based approaches, including single cell sorting, multicolour phenotyping (16‐18 colours), multi‐way sorting, conccurrent sorting and ies ies phenotyping, apoptosis and proliferation assays, cell viability monitoring, assay development et cetera.
t t The following equipment is availabble as a service:
i i Attune NxT flow acoustic cytometer BD Arialll cell sorter BD Fortessa fow cytometer (four): 3 laser, 18 colour high speed flow analyser BD FACSantoll flow cytometer: 3 laser, 8 colour analyser BD Influx cell sorters BD FACSaria Fusion cell sorters with 16+ fluorescent channels BD FACSJazz cell sorter BD FACSCalibur cell analyser BD FACSMelody cell sorter Cellomics Arrayscan XTI automated cellular imaging and analysis Coulter Multisizer 3 flow cytometeer for cell size & concentration Leica Sp5 confocal Leica LMD6 laser capture microdissection microscope Leica SPE Confocal Leica LM Cellomics Arrayscan XTI high‐throughput screening microscope Opera Phoenix (Perkin Elmer) high content confocal Facil Facil SeaHorse XF96 measure OCR and ECAR of live cells in a 96‐well plate format Miltenyi AutoMACS Pro cell separator Symphony analyser (5 lasers, 28 detectors) MoFlo customised cell sorter Biorad S3 sorter Fortessa analyser e e Cyan analyser LSR II analyser Aria II sorter
Find us at https:// www.med.cam.ac.uk/nihr‐cambridge‐brc‐cell‐phenotyping‐‐hub/
Cor Cor 46 Imaging
The Wellcome‐MRC Cambridge Stem Cell Institute Advanced Microscope Facility is able to offer imaging technologies, training and support.
The variety of instruments and image analysis options in the facility ensure that we are able to meet many imaging requirements in‐house. We are able to provide invaluable tools for investigating cellular processes in both fixed and living cells in 2D and 4D. This is achieved by means of conventional imaging, HCS, confocal microscopy, time‐lapse, widefield & FRAP, FRET, FCS and FLIM.
We also offer post‐processing and image analysis tools for image volumes (deconvolution, 3D reconstruction, quantification) and assist users by developing custom analysis protocols.
Our range of equipment includes:
2x Leica SP5 TCS confocal microscopes Zeiss 710 confocal microscope with FLIM Zeiss 880 Multiphoton microscope Zeiss 700 confocal microscope Andor Revolution XD Spinning Disk confocal microscope Leica Matrix HCS screening/live cell imaging microscope Zeiss Imager fluorescence microscope GE Incell 2200 High Content Imager Essen Incucyte Zoom live cell imager Nikon Biostation IM live cell imager
CONTACT US: [email protected]
Facilities Computing
CITIID has a local high‐performance computing (HPC) cluster and is configured similar to the University of Cambridge HPC, to which it has access via two 10Gb links.
There are 200TB of networked data storage available, which is supported by a team of four people, led by Stuart Williams.
CONTACT US: [email protected]
47 Core Immuno‐ metabolism
The CITTID immuno‐metabolism facility offers cutting‐edge high resolution liquid chromatography mass spectrometry (LC‐MS) to solve small molecule (less than 2000 Da)
analytical needs. Whether you are interested in highly bespoke hypothesis driven work, absolute quantitation, tracking stable labelled substrates through core metabolic pathways or untargeted global metabolomic profiling with fragmentation based metabolite ID, the immuno‐metabolism facility can tailor the analysis to your needs.
We also have a suite of data processing packages to deliver fast turnaround and get the most information out of your data from large scale pattern recognition studies to small scale quantitative work.
We currently use Thermo Scientific orbitrap (FTMS) based high‐resolution MS coupled to a best‐in‐class Vanquish UHPLC+ chromatography system for conventional analytes such as lipids and less polar aqueous compounds, and a Dionex Ion Chromatography system for highly polar difficult to measure species.
With over 15 years’ experience in the field of small molecule MS we can meet any analytical challenge. The following equipment is available: Thermo Scientific Q‐Exactive Plus Orbitrap mass spectrometer Thermo Scientific Horizon UHPLC+ liquid chromatography Thermo Scientific Integrion ion chromatography system Software: Excalibur V4.1, Tracefinder Clinical V4.1, Comound Discoverer V2.1
CONTACT US: [email protected]
Facilities Bio ‐ Safety Level 3
CL‐3 containment facilities in CITIID allow scientists to work with non‐attenuated clinical organisms. As such, they provide a critical research capacity that allows investigators to study the emergence of lethal pathogens with global importance.
CONTACT US: [email protected]
Core 48 W H E R E T O FIND U S
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
Jeffrey Cheah Biomedical Centre
Cambridge Biomedical Campus
University of Cambridge
Puddicombe Way
Cambridge
CB2 0AW
www.citiid.cam.ac.uk
The CITIID Directory was First Published in April 2019
Information was correct at the time of publication