About Leishield

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.

 

Consortium

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).

schema-Consortium-organisation.jpeg

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.

Leishield-biomarker-discovery.jpeg

Project description

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.

Timeline-Project-Leishield.jpeg

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

 
 

Contacts

NAME, SURNAME
AFFILIATION
TEL / FAX / EMAIL
Sterkers Yvon
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 

yvon.sterkers@univ-montp1.fr

Volf Petr
Charles University in Prague Faculty of Science, Department of Parasitology Vinicna 7, Prague 2, 128 44 Czech Republic

Tel +4202.2195.1815 

Mobile: +4207.2584.0969 

Fax +4202.2491.9704 

volf@cesnet.cz

Harrat Zoubir
Institut Pasteur in Algeria Route du petit Staouèli Dély Ibrahim - Algiers Algeria

Tel +213.021.37.68.51 

zharrat@pasteur.dz 

zharrat@gmail.com

Laouini Dhafer
Institut Pasteur deTunis Laboratory of Immuno-Pathology,  Vaccinology and Molecular Genetics 13, place Pasteur 1002 Tunis-Belvedere Tunisia

Tel +216.71 845 415 ext 501-507 

Fax +216.71 791 833 

dhafer.laouini@pasteur.rns.tn 

dhafer_l@yahoo.ca

Lemrani Meryem
Institut Pasteur in Morocco 1, place Louis Pasteur Casablanca 20100 Morocco

Tel +212.661 46 48 18 

Fax +212.522 26 09 57 

meryem.lemrani@pasteur.ma 

meryem.lemrani@gmail.com

Mottram Jeremy
College of Medical, Veterinary and Life Sciences  University of Glasgow  120 University Place Glasgow G12 8TA UK

Tel +44 (0)1 41 330 3745 

jeremy.mottram@glasgow.ac.uk

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 

mmukhtar@tropmedicine.org

Notredame Cédric
Centre de Regulacio Genomica (CRG)  Dr. Aiguader, 88 08003 Barcelona Spain

Tel +34.93 316 02 71 

cedric.notredame@gmail.com

Paul Richard
Institut Pasteur Functional Genetics of Infectious Diseases Unit 25 Rue du Dr. Roux 75724 Paris cedex 15 France

Tel +33.1.40.61.36.26 

richard.paul@pasteur.fr

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

Tel +55.21 3865 8177 

Fax +55.21 3865 81 95 

porrozzi@ioc.fiocruz.br 

renato.porrozzi@gmail.com

Smyrli Despoina
Hellenic Pasteur Institute Molecular Parasitology Laboratory, Microbiology Department, 127 Bas. Sofias Avenue 115 21 Athens Greece

Tel +30.210 6478841 

pennysmirlis@gmail.com

Spaeth Gerald
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 

gerald.spaeth@pasteur.fr

Antoniou Maria
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

Tel +30.2810.394746 

Mobile: +30.6944.794446 

Fax +30.2810.394740 

antoniou@med.uoc.gr

Aoun Karim
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 

karim.aoun@pasteur.rns.tn

Bastien Patrick
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) 

patrick.bastien@univ-montp1.fr

Bouratbine Aïda
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 

aida.bouratbine@pasteur.rns.tn

Cruz Israel
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 

cruzi@isciii.es

Cupolillo Elisa
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 

ecupoli@ioc.fiocruz.br

Dujardin Jean-Claude
Institute of Tropical Medicine Dept of Biomedical Sciences, Head Molecular Parasitology Unit, Head Nationalestraat, 155 B-2000 Antwerpen Belgium

Tel +32.3.2476355
Fax +32.3.2476359
JCDujardin@itg.be

Guerfali Fatma
Institut Pasteur de Tunis Laboratory of Transmission,  Control and Immunobiology of Infections 13, place Pasteur 1002 Tunis Belvédère, Tunisia

Tel +216.52 657 331 

fatma.guerfali@pasteur.rns.tn

References

  1. Louzir H, Aoun K, Späth GF, Laouini D, Prina E, Victoir K and Bouratbine A (2013). "Les leishmanioses à travers le réseau des Instituts Pasteur." Med Sci 29(12):1151-60.

  2. Lindgren E, Andersson Y, Suk JE, Sudre B and Semenza JC (2012). "Public health. Monitoring EU emerging infectious disease risk due to climate change." Science 336(6080): 418-419.

  3. Menn B, Lorentz S and Naucke TJ (2010). "Imported and travelling dogs as carriers of canine vector-borne pathogens in Germany." Parasit Vectors 3: 34.

  4. Naucke TJ, Menn B, Massberg D and Lorentz S (2008). "Sandflies and Leishmaniasis in Germany." Parasitol Res 103 Suppl 1: S65-68.

  5. Aguado M, Espinosa P, Romero-Mate A, Tardio JC, Cordoba S and Borbujo J (2013). "Outbreak of cutaneous Leishmaniasis in Fuenlabrada, Madrid." Actas Dermosifiliogr 104(4): 334-342.

  6. Albuquerque PL, Silva Junior GB, Freire CC, Oliveira SB, Almeida DM, Silva HF, Cavalcante Mdo S and Sousa Ade Q (2009). "Urbanization of visceral Leishmaniasis (kala-azar) in Fortaleza, Ceara, Brazil." Rev Panam Salud Publica 26(4): 330-333.

  7. Costa CH (2008). "Characterization and speculations on the urbanization of visceral Leishmaniasis in Brazil." Cad Saude Publica 24(12): 2959-2963.

  8. Hotez PJ, Savioli L and Fenwick A (2012). "Neglected tropical diseases of the Middle East and North Africa: review of their prevalence, distribution, and opportunities for control." PLoS Negl Trop Dis 6(2): e1475.

  9. Masmoudi A, Ayadi N, Boudaya S, Meziou TJ, Mseddi M, Marrekchi S, Bouassida S, Turki H and Zahaf A (2007). "[Clinical polymorphism of cutaneous Leishmaniasis in centre and south of Tunisia]." Bull Soc Pathol Exot 100(1): 36-40.

  10. Zaraa I, Ishak F, Kort R, El Euch D, Mokni M, Chaker E and Ben Osman A (2010). "Childhood and adult cutaneous Leishmaniasis in Tunisia." Int J Dermatol 49(7): 790-793.

  11. Acestor N, Masina S, Ives A, Walker J, Saravia NG and Fasel N (2006). "Resistance to oxidative stress is associated with metastasis in mucocutaneous Leishmaniasis." J Infect Dis 194(8): 1160-1167.

  12. Goyal N, Roy U and Rastogi AK (1996). "Relative resistance of promastigotes of a virulent and an avirulent strain of Leishmania donovani to hydrogen peroxide." Free Radic Biol Med 21(5): 683-689.

  13. Bacellar O, Lessa H, Schriefer A, Machado P, Ribeiro de Jesus A, Dutra WO, Gollob KJ and Carvalho EM (2002). "Up-regulation of Th1-type responses in mucosal Leishmaniasis patients." Infect Immun 70(12): 6734-6740.

  14. Giudice A, Camada I, Leopoldo PT, Pereira JM, Riley LW, Wilson ME, Ho JL, de Jesus AR, Carvalho EM and Almeida RP (2007). "Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to nitric oxide correlates with disease severity in Tegumentary Leishmaniasis." BMC Infect Dis 7: 7.

  15. Aoun K, Chouihi E, Amri F, Ben Alaya N, Raies A, Mary C and Bouratbine A (2009). "Short report: Contribution of quantitative real-time polymerase chain reaction to follow-up of visceral Leishmaniasis patients treated with meglumine antimoniate." Am J Trop Med Hyg 81(6): 1004-1006.

  16. Lira R, Sundar S, Makharia A, Kenney R, Gam A, Saraiva E and Sacks D (1999). "Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani." J Infect Dis 180(2): 564-567.

  17. Jeddi F, Piarroux R and Mary C (2011). "Antimony resistance in Leishmania, focusing on experimental research." J Trop Med 2011: 695382.

  18. Guimond C, Trudel N, Brochu C, Marquis N, El Fadili A, Peytavi R, Briand G, Richard D, Messier N, Papadopoulou B, Corbeil J, Bergeron MG, Legare D and Ouellette M (2003). "Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays." Nucleic Acids Res 31(20): 5886-5896.

  19. Singh R, Kumar D, Duncan RC, Nakhasi HL and Salotra P (2010). "Overexpression of histone H2A modulates drug susceptibility in Leishmania parasites." Int J Antimicrob Agents 36(1): 50-57.

  20. Guilvard E, Rioux JA, Gallego M, Pratlong F, Mahjour J, Martinez-Ortega E, Dereure J, Saddiki A and Martini A (1991). "[Leishmania tropica in Morocco. III--The vector of Phlebotomus sergenti. Apropos of 89 isolates]." Ann Parasitol Hum Comp 66(3): 96-99.

  21. Pratlong F, Rioux JA, Dereure J, Mahjour J, Gallego M, Guilvard E, Lanotte G, Perieres J, Martini A and Saddiki A (1991). "[Leishmania tropica in Morocco. IV--Intrafocal enzyme diversity]." Ann Parasitol Hum Comp 66(3): 100-104.

  22. Fellah H, Rhajaoui M, Ouahabi S, Belghiti D and Lyagoubi M (2007). "Occurence of human cutaneous Leishmaniasis in Zougha My Yacoub province (Morocco)." Int J Agri & Biol 1: 197-198.

  23. Guessous-Idrissi N, Chiheb S, Hamdani A, Riyad M, Bichichi M, Hamdani S and Krimech A (1997). "Cutaneous Leishmaniasis: an emerging epidemic focus of Leishmania tropica in north Morocco." Trans R Soc Trop Med Hyg 91(6): 660-663.

  24. Rhajaoui M, Nasereddin A, Fellah H, Azmi K, Amarir F, Al-Jawabreh A, Ereqat S, Planer J and Abdeen Z (2007). "New clinico-epidemiologic profile of cutaneous Leishmaniasis, Morocco." Emerg Infect Dis 13(9): 1358-1360.

  25. Ajaoud M, Es-sette N, Hamdi S, El-Idrissi AL, Riyad M and Lemrani M (2013). "Detection and molecular typing of Leishmania tropica from Phlebotomus sergenti and lesions of cutaneous Leishmaniasis in an emerging focus of Morocco." Parasit Vectors 6: 217.

  26. Antoniou M, Gramiccia M, Molina R, Dvorak V and Volf P (2013). "The role of indigenous phlebotomine sandflies and mammals in the spreading of Leishmaniasis agents in the Mediterranean region." Euro Surveill18(30).

  27. Antoniou M, Haralambous C, Mazeris A, Pratlong F, Dedet JP and Soteriadou K (2008). "Leishmania donovani Leishmaniasis in Cyprus." Lancet Infect Dis 8(1): 6-7.

  28. Mazeris A, Soteriadou K, Dedet JP, Haralambous C, Tsatsaris A, Moschandreas J, Messaritakis I, Christodoulou V, Papadopoulos B, Ivovic V, Pratlong F, Loucaides F and Antoniou M (2010). "Leishmaniases and the Cyprus paradox." Am J Trop Med Hyg 82(3): 441-448.

  29. Alam MZ, Haralambous C, Kuhls K, Gouzelou E, Sgouras D, Soteriadou K, Schnur L, Pratlong F and Schonian G (2009). "The paraphyletic composition of Leishmania donovani zymodeme MON-37 revealed by multilocus microsatellite typing." Microbes Infect 11(6-7): 707-715.

  30. Gouzelou E, Haralambous C, Amro A, Mentis A, Pratlong F, Dedet JP, Votypka J, Volf P, Toz SO, Kuhls K, Schonian G and Soteriadou K (2012). "Multilocus microsatellite typing (MLMT) of strains from Turkey and Cyprus reveals a novel monophyletic L. donovani sensu lato group." PLoS Negl Trop Dis 6(2): e1507.

  31. Messaritakis I, Christodoulou V, Mazeris A, Koutala E, Vlahou A, Papadogiorgaki S and Antoniou M (2013). "Drug resistance in natural isolates of Leishmania donovani s.l. promastigotes is dependent of Pgp170 expression." PLoS One 8(6): e65467.

  32. Haralambous C, Antoniou M, Pratlong F, Dedet JP and Soteriadou K (2008). "Development of a molecular assay specific for the Leishmania donovani complex that discriminates L. donovani/Leishmania infantum zymodemes: a useful tool for typing MON-1." Diagn Microbiol Infect Dis 60(1): 33-42.

  33. Ochsenreither S, Kuhls K, Schaar M, Presber W and Schonian G (2006). "Multilocus microsatellite typing as a new tool for discrimination of Leishmania infantum MON-1 strains." J Clin Microbiol 44(2): 495-503.

  34. Desjeux P (2004). "Leishmaniasis: current situation and new perspectives." Comp Immunol Microbiol Infect Dis27(5): 305-318.

  35. de Beer P, el Harith A, Deng LL, Semiao-Santos SJ, Chantal B and van Grootheest M (1991). "A killing disease epidemic among displaced Sudanese population identified as visceral Leishmaniasis." Am J Trop Med Hyg44(3): 283-289.

  36. El Tai NO, El Fari M, Mauricio I, Miles MA, Oskam L, El Safi SH, Presber WH and Schonian G (2001). "Leishmania donovani: intraspecific polymorphisms of Sudanese isolates revealed by PCR-based analyses and DNA sequencing." Exp Parasitol 97(1): 35-44.

  37. Zijlstra EE and el-Hassan AM (2001). "Leishmaniasis in Sudan. Visceral Leishmaniasis." Trans R Soc Trop Med Hyg 95 Suppl 1: S27-58.

  38. Zijlstra EE and el-Hassan AM (2001). "Leishmaniasis in Sudan. Post kala-azar dermal Leishmaniasis." Trans R Soc Trop Med Hyg 95 Suppl 1: S59-76.

  39. el-Hassan AM and Zijlstra EE (2001). "Leishmaniasis in Sudan. Mucosal Leishmaniasis." Trans R Soc Trop Med Hyg 95 Suppl 1: S19-26.

  40. Elamin EM, Guizani I, Guerbouj S, Gramiccia M, El Hassan AM, Di Muccio T, Taha MA and Mukhtar MM (2008). "Identification of Leishmania donovani as a cause of cutaneous Leishmaniasis in Sudan." Trans R Soc Trop Med Hyg 102(1): 54-57.

  41. Lachaud L, Bourgeois N, Kuk N, Morelle C, Crobu L, Merlin G, Bastien P, Pages M and Sterkers Y (2013). "Constitutive mosaic aneuploidy: a unique genetic feature widespread in the Leishmania genus." Microbes Infect.

  42. Sterkers Y, Lachaud L, Crobu L, Bastien P and Pages M (2011). "FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major." Cell Microbiol 13(2): 274-283.

  43. Sterkers Y, Lachaud L, Bourgeois N, Crobu L, Bastien P and Pages M (2012). "Novel insights into genome plasticity in Eukaryotes: mosaic aneuploidy in Leishmania." Mol Microbiol 86(1): 15-23.

  44. Pescher P, Blisnick T, Bastin P and Spath GF (2011). "Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation." Cell Microbiol 13(7): 978-991.

  45. Melby PC, Chandrasekar B, Zhao W and Coe JE (2001). "The hamster as a model of human visceral Leishmaniasis: progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response." J Immunol 166(3): 1912-1920.

  46. Harrat Z, Pratlong F, Belazzoug S, Dereure J, Deniau M, Rioux JA Belkaid M, Dedet JP (1996). Leishmania infantum and leishmania major in Algeria. Trans R Soc Trop Med and Hyg T: 90:625-629.

  47. Harrat Z, Boubidi SC, Pratlong F, Benikhlef R, Selt B, Dedet JP, Ravel C, Belkaid M (2009). Description of Leishmania close to L killicki (Rioux, Lanotte et Pratlong, 1986) in Algeria. Trans R Soc Trop Med and Hyg103:716-720.

  48. Izri MA, Belazzoug S, Pratlong F, Rioux JA (1992). Isolement de L. major chez Phlebotomus papatasi à Biskra (Algérie), fin d’une épopée éco-épidémiologique. Ann Parasitol Hum Comp 67(1):31-2.

  49. Boubidi SC, Benallal K, Boudrissa A, Bouiba L, Bouchareb B, Garni R, Bouratbine A, Ravel C, Pestova J, Dvorak V, Votypka J, Volf P & Harrat Z (2011). Phlebotomus sergenti (Parrot, 1917) identified as Leishmania killicki hosts in Ghardaïa, south Algeria. Microbes and Infection 13(7):691-696. 

  50. Boudrissa A, Cherif K, Kherrachi I, Benbetka S, Bouiba L, Boubidi SC, Benikhlef R, Arrar L, Hamrioui B & Harrat ZH (2012). Extension de Leishmania major au Nord de l’Algérie. Bull Soc Path Exot 105(1):30-35. 

  51. Alvar J et al. (2012). Leishmaniasis worldwide and global estimates of its incidence. PLoS One 7, e35671.

  52. Relevé Epidémiologique Mensuel (REM), Vol XXII, annuel 2012. Institut National de Santé Publique . 

  53. Tomas-Pérez M, Khaldi M, Riera C et al (2014). First report of natural infection in hedgehogs with Leishmania major, a possible reservoir of zoonotic cutaneous leishmaniasis in Algeria . Acta Tropica 135;44-49. 

  54. Cherif K , Boudrissa A, Hamdi Cherif MH, Harrat Z (2012). Un programme social pour la lutte physique contre la leishmaniose cutanée zoonotique dans la wilaya de M’sila en Algérie. Santé Publique 24(6):511-522. 

  55. Mollalo A, Alimohammadi A, Shahrisvand M, Reza Shirzadi M R, Malek MR (2014). Spatial and statistical analyses of the relations between vegetation cover and incidence of cutaneous leishmaniasis in an endemic province, northeast of Iran. Asian Pac J Trop Dis 4(3):176-180. 

  56. Toumi A, Chlif S, Bettaieb J et al (2012). Temporal dynamics and impact of climate factors on the incidence of zoonotic cutaneous leishmaniasis in Central Tunisia. Plos NTD 6:e1633. 

  57. Garni R, Tran A, Guis H, Baldet T, Benallal K, Boubidi SC & Harrat Z (2014). Remote sensing, land cover changes, and vector-borne diseases: Use of high spatial resolution satellite imagery to map the risk of occurrence of cutaneous leishmaniasis in Ghardaïa, Algeria. Infect. Genet. Evol 28:725-735 

  58. Bhunia GS, Kumar V, Kumar AJ, Das P, Kesari S (2010). The use of remote sensing in the identification of the eco-environmental factors associated with the risk of human visceral leishmaniasis (kala-azar) on the Gangetic plain, in north-eastern India. Ann Trop Med Parasitol 104(1):35–53 

  59. Delli G, Sarfatti P. Cadi A (2002). Classification of historical series of NDVI: an application for northern Algeria. Journal of Agriculture and environment for international development 

  60. 96, o. ¾.

 
flag-of-Europe.PNG

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement N°778298.