Immunology and Immunopathology of visceral leishmaniasis

Lead Research Organisation: University of York
Department Name: Biology

Abstract

Leishmaniasis is a disease caused when people are bitten by sandflies that contain a small single cell parasite, called Leishmania. Although some people never get sick, many develop local skin ulcers or a potentially fatal disease that affects the internal organs, called visceral leishmaniasis (kala azar or ?black sickness?). Why different people get different types of disease is not known, but it may relate to the type of Leishmania they are infected with and their health of their immune system. 2 million people get leishmaniasis every year (in 88 countries, including some in Europe) and visceral leishmaniasis is responsible for over 60,000 deaths annually. As the parasites live deep in the tissues (spleen, liver, bone marrow), it is difficult in sick people to see exactly how they are affecting our immune system and to find ways to improve how the immune system deals with them. Therefore, we need to use experimental models of the disease to study these questions. Although much progress has been made, experimental models cannot provide the whole picture and there may be important differences in how mice and people respond to these parasites, or in how much damage the immune system does to our organs trying to fight the infection. We wish to conduct an integrated research programme to let us study disease processes in human and mouse tissues side by side. This approach is important, both to see whether the responses in mice also occur in man (thus supporting clinical study of drugs/vaccines developed in mice) and conversely to see whether we can improve the predictive nature of models used for testing drugs/vaccines. We will be studying how Leishmania is eaten by white blood cells (phagocytes) in the liver, and how the expression of our genes changes in response to the infection. We will develop new microscopy approaches that allow us to see how infection affects phagocyte function and their ability to coordinate inflammation. We will use tissues samples taken from people during treatment and also at post mortem, to observe how well their immune systems have responded to treatment or to understand what went wrong that led to their death. In combination, these studies will provide much important new information on human disease, and help to reduce and improve the quality of animal experimentation.

Technical Summary

Leishmaniasis represents a spectrum of diseases associated with infection by the protozoan parasite, Leishmania. Of global importance, with approximately 2M new cases reported annually from 88 countries, leishmaniasis ranks high amongst parasitic diseases for its impact on public health. Visceral leishmaniasis (VL), caused by L. donovani and L. infantum/chagasi is a leading cause of parasite-associated mortality. Research on VL thus holds potential for major benefits to health. In addition, the study of this intracellular parasite continues to increase our fundamental understanding of the host-parasite interface and immune function. Building on the exciting achievements of our previous MRC supported research, we now seek to develop a fully-integrated programme, using animal models, human liver-slice culture and clinical histopathology, to explore the diverse roles played by mononuclear phagocytes in VL (as host, regulator of inflammation / immunity, and mediator of pathology).



To study the biology of tissue-resident macrophages in their natural environment, we will define (at the molecular and cellular level) the in situ response of murine and human Kupffer cells to L. donovani infection and the downstream consequences for the initiation of inflammation. We will perform comparative mRNA and miRNA profiling of human and mouse Kupffer cells, and validate potential mediators of inflammation using dynamic imaging approaches in human and murine liver. New tools will allow us to examine the function of Kupffer cells in established granulomas in mice. We will perform comparative histopathology of spleen / LN from mice and patients with VL, to determine whether the lymphoid tissue remodelling associated with parasite persistence and immunosuppression in mice is also evident in human disease, and using intra-vital imaging in combination with mice that allow cell-specific and temporal depletion and lineage tracing, we will define the involvement of mononuclear phagocytes in this process. Informed by histopathology and transcriptional profiling, we will develop new models of hepatic infection that reflect more closely the diversity of response seen in man. Likewise, we will exploit recently identified sites of cryptic infection in mice to develop a greater understanding of the mechanisms underlying post kala azar dermal leishmaniasis, mucosal disease and secondary infection.



Collectively, the data generated in this Programme will test a number of new hypotheses related to mononuclear phagocyte function in VL, help to cross-validate existing and new mouse models and, by providing new comparative data on disease pathogenesis, increase the likelihood of effective translation of our research into new prophylactic or therapeutic interventions.

Publications

10 25 50
 
Description CRACK-IT Phase 1
Amount £100,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 12/2013 
End 06/2014
 
Description CRACK-IT Phase 2
Amount £996,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 01/2015 
End 12/2017
 
Description MRC UK-Brazil Joint centre Partnership
Amount £2,000,000 (GBP)
Funding ID MR/S019472/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2022
 
Description Project grant
Amount $150,000 (USD)
Organisation Foundation for Sarcoidosis Research 
Start 10/2017 
End 09/2019
 
Description RCUK GCRF Foundation Award
Amount £600,281 (GBP)
Funding ID MR/P024661/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description STROMA
Amount € 900,000 (EUR)
Funding ID 289720 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2012 
End 12/2015
 
Description Senior Investigator Award
Amount £2,300,000 (GBP)
Funding ID 32470 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Description Translation Award
Amount £1,600,000 (GBP)
Funding ID WT108518MA 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 10/2020
 
Description Wellcome ISSF
Amount £30,000 (GBP)
Organisation University of York 
Sector Academic/University
Country United Kingdom
Start 04/2012 
End 03/2013
 
Description Wellcome ISSF
Amount £30,000 (GBP)
Organisation University of York 
Sector Academic/University
Country United Kingdom
Start 06/2013 
End 01/2014
 
Title LeisPathNet digital pathology platform 
Description We have developed a website to host digitised whole slide images from research projects on human and experimental leishmaniasis. The database is being developed in collaboration with Zeiss and allows searching of images via metadata to allow within and across experiment analysis of pathology data. Metadata also includes available tissue samples for future research, allowing the development of new clinical and animal research collaborations based on archival rather than new sample collection. This has considerable ethical implications, notably in the context of 3Rs and maximising benefit from human donations. 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? Yes  
Impact Whilst still in early pilot phase, we anticipate significant engage, et from the leishmanisis research community, promoting greater global collaboration and enhanced access to clinical and animal tissues and greater opportunities for data sharing and mining. 
URL https://leishpathnet.org
 
Title Macrophage transcriptomes 
Description Transcriptomes of Kupffer cells isolated from naive and infected mice: E-MEXP-3877 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact none to date 
URL http://www.ebi.ac.uk/arrayexpress/
 
Title Multiscale model of leishmaniasis 
Description In silico model of leishmaniasis immune response in systemic tissue (LeishSim) developed as part of Phase 2 funding 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2017 
Provided To Others? No  
Impact The in silico model is currently in final stages of testing and will be available online for open access and use by the research community in mid 2018. 
URL https://www.leishsim.org/#home-tab
 
Title LeishPathNet 
Description A web based collection of digital pathology images from human and animal studies associated with research on leishmaniasis. The data is fully searchable via associated metadata and the web site promotes collaboration by making tissues available for collaborative research projects. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Too early to indicate 
URL https://leishpathnet.org
 
Title LeishSim v1.1 
Description A pilot version of a leishmaniasis drug - immune simulator for reducing animal usage in leishmaniasis drug development 
Type Of Material Computer model/algorithm 
Provided To Others? No  
Impact Award of CRACK IT Phase 2 funding from NC3Rs 
 
Description Cybula 
Organisation Cybula
Country United Kingdom 
Sector Private 
PI Contribution SME collaborator in CRACKIT Phase 1 and 2 awards. Management and immunology from York
Collaborator Contribution They provide computational, cloud data sharing and software design expertise
Impact Successful Phase 2 CRACKIT Challenge award
Start Year 2013
 
Description DNDi 
Organisation Drugs for Neglected Diseases initiative (DNDi)
Country Switzerland 
Sector Private 
PI Contribution DNDi leads international efforts in drug development for leishmaniasis. We will provide an evidence base for DNDi to design new clinical trials of leishmaniasis combination therapy
Collaborator Contribution DNDi will provide clinical data to parameterise our models and provide access to new chemical entities for in vivo evaluation in models
Impact Successful award of CRACK-IT Phase 1 grant
Start Year 2013
 
Description Glasgow 
Organisation Wellcome Trust
Department Wellcome Trust Centre for Molecular Parasitology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration for Phase 1 and Phase 2 CRACKIT Challenge funding. Management and immunology from York
Collaborator Contribution Molecular parasitology expertise from Glasgow
Impact Successful Phase 2 CRACKIT Challenge award
Start Year 2013
 
Description LSHTM 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Research collaboration on joint CRACK-IT Phase 1 and Phase 2 projects. Project management and immunology expertise provided by York
Collaborator Contribution Drug discovery and PKPD analysis provided by LSHTM
Impact Award of Phase 2 CRACKIT Challenge grant
Start Year 2013
 
Description MRC Tissue Remodeling and Fibrosis Research Consortium 
Organisation Medical Research Council (MRC)
Department The Mary Lyon Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Multiple partner (`30) across UK linked to mouse phenotyping programme at Mary Lyons Centre
Collaborator Contribution None to date
Impact Networking meetings
Start Year 2012
 
Description MRC Tissue Remodeling and Fibrosis Research Consortium 
Organisation University College London
Department Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Multiple partner (`30) across UK linked to mouse phenotyping programme at Mary Lyons Centre
Collaborator Contribution None to date
Impact Networking meetings
Start Year 2012
 
Description MRC Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Public 
PI Contribution Multiple partner (`30) across UK linked to mouse phenotyping programme at Mary Lyons Centre
Collaborator Contribution None to date
Impact Networking meetings
Start Year 2012
 
Description MRC Tissue Remodeling and Fibrosis Research Consortium 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Multiple partner (`30) across UK linked to mouse phenotyping programme at Mary Lyons Centre
Collaborator Contribution None to date
Impact Networking meetings
Start Year 2012
 
Description PKDL 
Organisation Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital
Department Department of Pharmacology
Country India 
Sector Academic/University 
PI Contribution Collaborative research on histopathology of PKDL
Collaborator Contribution Collaborative research on histopathology of PKDL
Impact Publications in preparation
Start Year 2012
 
Description PKDL Sudan 
Organisation Institute for Endemic Diseases IEND
Country Sudan 
Sector Academic/University 
PI Contribution Histopathology of PKDL and vaccine development
Collaborator Contribution Histopathology of PKDL and vaccine development
Impact Grant applications pending
Start Year 2012
 
Description Pharmidex 
Organisation Pharmidex
Country United Kingdom 
Sector Private 
PI Contribution SME partner for Phase 1 and 2 CRACKIT Challenge awards. Management and immunology from York
Collaborator Contribution Drug PKPD evaluation from Pharmidex
Impact Successful Phase 2 CRACKIT Challenge Award
Start Year 2013
 
Description STROMA 
Organisation Cantonal Hospital St. Gallen
Department Institute of Immunobiology; Kantonsspital St.Gallen
Country Switzerland 
Sector Hospitals 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation Erasmus University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation Materiomics
Country Netherlands 
Sector Private 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation Max Planck Society
Department Max Planck Institute of Biochemistry
Country Germany 
Sector Public 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation Milenia Biotec GmbH
Country Germany 
Sector Private 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation ProBioGen AG
Country Germany 
Sector Private 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation University of Lisbon
Department Institute for Molecular Medicine
Country Portugal 
Sector Academic/University 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation University of Strasbourg
Department Immunology
Country France 
Sector Academic/University 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description STROMA 
Organisation University of Zurich
Department Institute of Oral Biology
Country Switzerland 
Sector Academic/University 
PI Contribution Co-ordinator of Marie Curie Integrated Training Network
Collaborator Contribution Members of Marie Curie ITN
Impact Employment of 13 ESRs and 3 ERs
Start Year 2012
 
Description Silence 
Organisation Silence Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution in vivo imaging
Collaborator Contribution RNAi targeting methodology
Impact none to date
Start Year 2013
 
Description SimOmics 
Organisation Sim Omics
Country United Kingdom 
Sector Private 
PI Contribution SME collaborator in Phase 1 and 2 CRACKIT Challenge awards. Management and immunology provided by York
Collaborator Contribution They provide computational and software development expertise
Impact Successful Phase 2 CRACKIT Challenge award
Start Year 2013
 
Description UFRJ Brazil (Newton) 
Organisation Federal University of Rio de Janeiro
Country Brazil 
Sector Academic/University 
PI Contribution Collaborative Newton award (UK PI Mottram Glasgow)
Collaborator Contribution collaboration on transcriptomics
Impact workshop on computational immunology at UFRJ; transfer of biological samples
Start Year 2015
 
Description VL Brazil (Newton) 
Organisation Federal University of Pelotas (UFPel)
Country Brazil 
Sector Academic/University 
PI Contribution Newton CONFAP funded collaborative award (PI UK Mottram York); input into experimental design
Collaborator Contribution access to clinical samples and prospects for new clinical research programs
Impact None to date
Start Year 2015
 
Title LEISH1 
Description Therapeutic adenoviral vectored leishmaniasis vaccine. Re-fundd for Phase2 trials by Wellcome Trust in 2015 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact safety and first human immunogenicity data on leishmanial antigens 
URL http://www.isrctn.com/ISRCTN07766359
 
Title LEISH2a 
Description Phase IIa trial of therapeutic vaccine in Sudan 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Additional funding being sought for prophylactic vaccine development. 
URL http://www.wellcome.ac.uk/Funding/Innovations/Funded-projects/Vaccine/index.htm
 
Description Conference stand 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Exhibitor stand at Worldleish 2017 a major international conference for researchers working on leishmaniasis, held in Toledo, Spain in May 2017. The stand was fully manned throughout the conference and demonstrated the value of in silico modelling, provided pilot demonstrations of LeishSim and gave exposure to NC3Rs and general 3Rs issues in research.
Year(s) Of Engagement Activity 2017
URL http://www.worldleish2017.org
 
Description EU Researchers Night 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Attended stand at EU Researchers Night, communicating work on leishmaniasis and computational modelling
Year(s) Of Engagement Activity 2015
 
Description Festival of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 200+ visitors to a city centre exhibition on research on chronic diseases

increased profile for MRC related research
Year(s) Of Engagement Activity 2012,2013
 
Description Festival of Science 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Stand and visual displays on research program and NC3Rs activity in pavilion erected in centre of York. Footfall of approx. 300, with children playing with robots and adults learning about simulations of infectious disease as a means for reducing animal usage in drug development. High level of public engagement through curiosity driven play and question with subsequent discussion. Increased awareness of neglected tropical diseases

Follow up engagement activities planned and subsequently delivered
Year(s) Of Engagement Activity 2014
URL http://yorkfestivalofideas.com/2014/
 
Description Festival of Science 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Attended stand at festival of Science communicating work on leishmaniasis and computational modelling
Year(s) Of Engagement Activity 2015
 
Description Tour Grand Depart 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact NC3Rs stand at the University of York exhibition pavilion at the Tour de France Grand depart allowed exposure of 3Rs principles and the work funded by The CRACKIT Challenge to be highlighted to ~2000 attendees, including demonstration of robot simulators of immunity. The case for research and development for fighting neglected tropical disease was also made . Throughout the day, these pics prompted questions and curiosity from all age groups.

Increased awareness by many of the major issues in the fight against neglected diseases and how concerted efforts by interdisciplinary teams can address these, with additional 3Rs added value.
Year(s) Of Engagement Activity 2014
URL http://www.york.ac.uk/computational-immunology/news/ycilattdf/
 
Description YorNight 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Stand and visual displays on research program and NC3Rs activity in pavilion in centre of York. Footfall of approx. 300, with children playing with robots and adults learning about simulations of infectious disease as a means for reducing animal usage in drug development. High level of public engagement through curiosity driven play and question with subsequent discussion. Increased awareness of neglected tropical diseases

Many questions and responses indicating public awareness and understanding of why animals are used in research and ongoing £Rs research programs in York and elsewhere
Year(s) Of Engagement Activity 2014
URL http://www.york.ac.uk/cii/news/markcoles-sept14/