The LeiSHield Project
Protozoan parasites of the genus Leishmania generate severe human diseases termed Leishmaniases. Due to their frequency and the severity of certain clinical forms, these diseases represent a major public health problem and limit the economic growth in various developing countries. The presence of Pasteur Institutes in countries endemic for Leishmaniasis has provided important incentives to develop a strong public health agenda in the Pasteur scientific community with respect to these important diseases. A concerted effort is now coordinated through the recently created LeishRIIP platform (www.leishriip.org), which aims to identify synergies and complementarities between the 9 members of the Institute Pasteur International Network (IPIN) working on various aspects of the disease including epidemiology, diagnosis, chemotherapy and vaccination.
A round table discussion on LeishRIIP held at the WorldLeish5 meeting (Brazil 2013) called for a defined agenda to allow the emergence of a cutting-edge transversal research project between LeishRIIP partner labs. This project should combine the unique field expertise of partners from endemic countries, with the systems-level and high throughput technologies available at Institut Pasteur in Paris and its collaboration partners, which then will feed back information to these ‘endemic’ institutes for the validation and translation of potential diagnostic bio-markers, new drug targets, and/or vaccine candidates.
This transversal project, which we termed LeiSHield aims to investigate the epidemiology and anticipate the emergence of cutaneous (CL) and visceral Leishmaniasis (VL) in endemic countries in the Mediterranean region and non-endemic countries of the EU, and to assess the risk and spread of urbanizing Leishmaniasis in South America.
Structure. For this pilot study, LeiSHield will be structured into two complementary clusters with expertise in field studies and molecular epidemiological assessment (Cluster 1), and high throughput sequencing analysis linked to bio-informatics data processing (Cluster 2) (see Figure 1).
Each cluster is coordinated by a dedicated cluster leader and includes defined transversal WPs that are directed by partners from IP Tunis (PI: Dhafer Laouini, IPT-a, WP1; PI: Aïda Bouratbine, IPT-b, WP2), IP Morocco (PI: Meryem Lemrani, WP3), Hellenic Pasteur Institute (PI: Despina Smirlis, WP4), ISCIII (PI: Israel Cruz, WP5), FioCruz (PI: Elisa Cupolillo, WP6), the University of Glasgow (UG) (coPIs: Jeremy Mottram and Maowia Mukhtar, WP7), CNRS (PI: Patrick Bastien, WP8), IP Paris (PI: Gerald Spaeth, IPP-a WP9; PI: Anavaj Sakuntabhai, IPP-b, WP10; Richard Paul, IPP-b, WP11), and CRG (PI: Cedric Notredame, WP12) (Figures 1 and 2). By combining the complementary expertise of LeiSHield partners in (i) collection of isolates, patient material, and sand flies, (ii) their phenotypic and molecular epidemiological characterization, (iii) the systems-wide and bio-informatics analysis of their genomic and transcriptomic profiles and (iv) the biological validation of in silico-generated hypotheses, our consortium will establish a unique and powerful new pipeline for the discovery of intra- and inter-species biomarkers with relevance to parasite pathogenicity, drug resistance and vector competence, and host susceptibility.
Complementarity. The LeiSHield consortium will combine complementary expertise of (i) LeishRIIP members and experts in disease-endemic countries that have access to patient samples, vectors, reservoirs, and parasite field isolates, and are already actively involved in Leishmaniasis surveillance and epidemiology in their respective countries, (ii) LeishRIIP members and experts with access to cutting-edge technologies and infrastructures for throughput capable systems-wide genomics, transcriptomics, proteomics analyses, genetic manipulation, computation, and bio-informatics, and (iii) non-profit organizations and strong industrial partners with interest in pre-clinical and clinical development to translate LeiSHield findings into application for animal and human diagnostics, vaccination, or chemotherapy.
In 2012, VL was declared as new emerging disease in Europe with expected important public health impact due to climate change (2). The risk of Leishmania epidemics in the Maghreb and East Europe, and its northward spread is further supported by recent studies on sand fly distribution and on the detection of L. infantum and L. donovani in previously non-endemic areas (3; 4). Likewise, urbanization of Leishmaniasis in Europe and South America has been recognized as a new major Public Health issue (5; 6; 7). Furthermore, the increasing rate of immigration from endemic countries in North and East Africa and the Middle East to Europe significantly enhances the risk of Leishmaniasis emergence. LeiSHield will apply high throughput DNA and RNA sequencing on human samples, insect vectors, and parasite field isolates obtained from infected dogs and humans to (i) assess parasite genomic diversity and hybridization, (ii) correlate parasite genotypes with pathology and treatment outcomes, (iii) monitor distribution of sand fly and Leishmania species, and (iv) identify human resistance/susceptibility gene loci for Leishmaniasis.
This very ambitious research program on genotype-genotype interactions between parasites, vectors, human hosts and animal reservoirs will place LeishRIIP on the forefront of current system epidemiology research. The LeiSHield project will emerge over the next 24 months following three phases (Figure 1). First, we will conduct a pilot study that will bring together key actors and future leaders of the project and that will deliver the proof of concept on the Leishmania genomic variability and phenotypic consequences across all major parasite species and in various endemic regions (subject of this letter of intend) applying HT sequencing on selected field isolates that are prioritized by the biological and genetic tools already established in the partner labs. One major aim in the pilot phase is the standardization and exchange of protocols and technologies as well as the establishment of a functional infrastructure between partner institutes. Results obtained from Phase 1 (data, publications, infrastructure, standardized approaches) will render us highly competitive to obtain international funding and provide a strong framework for creation and expansion of the LeiSHield consortium. Phase 2 will be dedicated to (i) expanding the bio-banks of field isolates (parasite, vector, human materials, reservoir, human materials) from selected regions prioritized through the pilot phase, (ii) data collection on a systems-wide level by genomics, transcriptomics, and proteomics analyses of this material, (iii) data analysis and bio-marker discovery through bio-informatics and systems biological assessment, and (iv) mathematical modeling taking into account local transmission cycles, population structures (vector, reservoir, human), and ecological and political factors (climate, urbanization, migration). Phase 2 thus will provide important new information relevant for public health measures to better assess and anticipate risks associated with the emergence and urbanization of Leishmaniasis across the globe. The delivery of significant new intellectual property with respect to biomarker, drug target, vaccine candidate, and drug resistance gene discovery will then be translated into application in Phase 3 in collaboration with public, private and commercial partners.
Specific Aims and Impact
The current focus of this Pilot Project on the characterization of phenotypic variability of Leishmania field isolates and the underlying genomic diversity will provide a first framework to allow the establishment of a multi-disciplinary, international collaborative research program on the systems epidemiology of Leishmania infection. The ultimate goal of this project is to establish a risk map across endemic areas to inform authorities on the spread of the disease and shield non-endemic areas against emerging cutaneous and visceral Leishmaniasis. The specific aims their impact are:
1) To synergize complementary expertise available inside the LeishRIIP network in field studies and molecular epidemiology of Leishmania infection provided by partners from the “South”, and high-throughput sequencing, bio-informatics, and molecular parasitology expertise provided by partners from the “North”. This pilot study will (i) strengthen the research capacities in endemic countries, (ii) extend the rather isolated local research efforts on a regional and even global scale, and (iii) increase the significance of current molecular investigations by exploiting disease-relevant field isolates rather than culture-adapted model strains.
2) To establish a cutting-edge systems-wide approach applied on a major public health threat, which is novel in parasitic systems and will put IPIN and LeishRIIP at the forefront of infectious disease research. Interfacing epidemiology with genomic, transcriptomic, and proteomic analyses, and bio-informatics data mining, will allow important new insight into parasite-specific biology. Thus LeiSHield will have an important impact on our limited understanding of parasite intracellular infection, immune evasion, drug resistance, or host susceptibility to infection with relevance for disease prevention and therapy.
3) To efficiently translate research findings into pre-clinical and clinical application through public-private partherships. LeiSHield will significantly enhance the translational potential of neglected disease research inside the IPIN through its focus on bio-marker discovery. This will increase innovation potential, visibility and competitively of the IP research community and attract new financial resources and partners for pre-clinical investigations. The generation of new intellectual property through bio-marker discovery and their pre-clinical validation can be of commercial value and thus exploited for economic development. The application of bio-markers for prognostics and diagnostics, vaccination, and chemotherapy will have an important impact on the Public Health of disease-endemic countries.
4) To establish standardize protocols and procedures used to assess the epidemiology of Leishmaniasis in LeishRIIP partner countries. Standardization of methodology is a prerequisite to compare the dynamics of Leishmania infection across geographically very different regions and to elucidate how transmission, ecology, and population structure affect disease propagation and outcome. This will have a major impact on risk assessment and anticipation, and will inform health authorities to adapt their public health measures to environmental challenges (e.g. climate change or population migration).
5) To strengthen research capacities and open new training opportunities through networking actions, web tools, teaching courses, PhD and postdoc programs (financed for example by the IP ACIP and EU Marie Curie funding schemes), with the objective to transfer cutting edge know how and technology. This will have a major impact on the excellence of future scientific investigation inside IPIN.
The Work Packages
WP1: Identification of molecular determinants underlying parasite pathogenicity in Tunisian field isolates
PI: Dhafer Laouini, IP Tunis; WHO Collaborating Center for Leishmaniasis
WP2: Leishmania infantum genomic variability and phenotypic consequences on drug susceptibility
PI: Aïda Bouratbine, IP Tunis, LR 11-IPT-06 “Parasitoses médicales, Biotechnologies et Biomolécules”
WP3: Epidemiological investigation of L. tropica infection in Morocco
PI: Meryem Lemrani, IP Morocco
WP4: MLMT analysis of newly isolated anthroponotic L. donovani s.l. strains from Cyprus and correlation of genotypic profiles to tropism and drug resistance
PI: Despina Smirlis, Hellenic Pasteur Institute
WP5: Population genetics of Spanish L. infantum isolates from human origin and identification of virulence markers
PI: Israel Cruz, WHO Collaborating Center for Leishmaniasis, Servicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII) , Spain
WP6: Population genetics of Brazilian L. infantum isolates from endemic areas presenting distinct transmission cycle
PI: Elisa Cupolillo, Fundação Oswaldo Cruz (Fiocruz ), Brazil
WP7: Leishmania dovovani genome sequence diversity and disease tropism in the Sudan
co-PIs: Jeremy Mottram, The University of Glasgow (UoG), UK; Maowia Mukhtar, Institute of Endemic Diseases (IEND), Khartoum, Sudan
WP8: Genetics and epigenetics of the fluctuation of protein expression in Leishmania.
PI: Prof. Patrick Bastien, UMR MIVEGEC (CNRS 5290 - IRD 224 - Universités Montpellier 1 et 2)
WP9: Systems-wide analysis of Leishmania genomic and transcriptomic adaptation
PI: Gerald Spaeth, IP Paris
WP10: Human Genetic Susceptibility to Leishmaniasis
PI: Anavaj Sakuntabhai, IP Paris
WP11: Transmission epidemiology of Leishmaniasis
PI: Richard Paul, IP Paris
WP12: High Throughput Bioinformatics analysis
PI: Cedric Notredame, CRG, Barcelona
WP13: In situ genome sequencing: tracking genetic diversity of L. donovani directly in clinical samples
PI: Jean-Claude Dujardin, Institute of Tropical Medicine (ITM), Belgium
WP14 : Leishmania development in sand flies.
PI: Petr Volf , Charles University in Prague
WP15 : Environmental risk mapping of cutaneous leishmaniasis in Algeria.
PI: Zoubir Harrat , Institut Pasteur in Algeria
WP16 : Comparison of L. infantum MON-1 isolates from Cyprus (infecting dogs but no humans) to L. infantum MON-1 isolates from Crete (infecting both humans and dogs) a nd identification of virulence markers .
PI: Maria Antoniou , University of Crete Medical School, Greece
TEL / FAX / EMAIL
Département de Parasitologie-Mycologie UMR MIVEGEC (CNRS 5290 - IRD 224 - Universités Montpellier 1 et 2) C.H.R.U. de Montpellier 39 Avenue Charles Flahault 34295 Montpellier Cedex 5 France
Tel +33.4 67 33 23 50
Charles University in Prague Faculty of Science, Department of Parasitology Vinicna 7, Prague 2, 128 44 Czech Republic
Institut Pasteur in Algeria Route du petit Staouèli Dély Ibrahim - Algiers Algeria
Institut Pasteur deTunis Laboratory of Immuno-Pathology, Vaccinology and Molecular Genetics 13, place Pasteur 1002 Tunis-Belvedere Tunisia
Institut Pasteur in Morocco 1, place Louis Pasteur Casablanca 20100 Morocco
College of Medical, Veterinary and Life Sciences University of Glasgow 120 University Place Glasgow G12 8TA UK
Tel +44 (0)1 41 330 3745
Mukhtar Maowia M.
Department of Molecular Biology Institute of Endemic Diseases University of Khartoum P.O. Box 11463 Khartoum Sudan
Tel +249.912 234 268
Fax +249.183 77 97 12
Centre de Regulacio Genomica (CRG) Dr. Aiguader, 88 08003 Barcelona Spain
Tel +34.93 316 02 71
Institut Pasteur Functional Genetics of Infectious Diseases Unit 25 Rue du Dr. Roux 75724 Paris cedex 15 France
Porrozzi de Almeida Renato
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Laboratory of Research on Leishmaniasis Av Brasil 4365, Manguinhos 21040-360 Rio de Janeiro Brazil
Hellenic Pasteur Institute Molecular Parasitology Laboratory, Microbiology Department, 127 Bas. Sofias Avenue 115 21 Athens Greece
Tel +30.210 6478841
Institut Pasteur Molecular Parasitology and Signaling Unit 25-28 rue du Dr Roux 75724 PARIS Cedex 15 France
Tel + 33.1 40 61 38 58
Fax + 33.1 45 68 83 32
University of Crete Medical School,Greece Assistant Professor of Parasitology, Head of the Microbiology Laboratory Laboratory of Clinical Bacteriology, Parasitology, Zoonoses and Tropical Medicine University of Crete, Faculty of Medicine, Voutes, 71003, Heraklion, Crete, Greece
Institut Pasteur de Tunis Laboratoire de Parasitologie-Mycologie, 13 place Pasteur BP 74 1002 Tunis Belvédère, Tunisia
Tel +216.71 890 827
Fax+216.71 791 833
Departement de Parasitologie-Mycologie Centre National de Reference des Leishmanioses Vice-Director, "MiVEGEC" unit research UMR5290 CNRS/224 IRD/UM1/UM2 Faculte de Medecine, Université Montpellier 1 39 Av. Charles Flahault 34295 Montpellier cedex 5 France
Tel +33.4 67 33 23 72 (direct)
Tel +33.4 67 33 23 50 (secretariat)
Institut Pasteur de Tunis Laboratoire de Parasitologie-Mycologie, 13 place Pasteur BP 74 1002 Tunis Belvédère, Tunisia
Tel +216.71 890 827
Fax +216.71 791 833
WHO Collaborating Centre for Leishmaniasis, Servicio de parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III Ctra. Majadahonda-Pozuelo Km2. 28229 Majadahonda, Madrid Spain
Tel +34.918 223 777
Fax +34.915 097 034
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz Laboratory of Research on Leishmaniasis Av Brasil 4365, Manguinhos 21040-360 Rio de Janeiro Brazil
Tel +55.21 3865 8177
Fax +55.21 3865 81 95
Institute of Tropical Medicine Dept of Biomedical Sciences, Head Molecular Parasitology Unit, Head Nationalestraat, 155 B-2000 Antwerpen Belgium
Institut Pasteur de Tunis Laboratory of Transmission, Control and Immunobiology of Infections 13, place Pasteur 1002 Tunis Belvédère, Tunisia
Tel +216.52 657 331
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This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement N°778298.