Despina Smirlis | Department of Microbiology
Scientific Team Leader
The main research activity of the group is focused on the study of the protozoan parasite Leishmania, the aetiological agent of the important disease leishmaniasis. The disease is characterized as anthropozoonotic and is transmitted by the bite of sandflies. Leishmaniasis is endemic in Greece, whereby the prevalence in dogs, the local reservoir host, is up to 34%. In humans leishmaniasis has different clinical manifestations, including cutaneous, mucocutaneous and visceral, the latter being the most severe form of disease, lethal if left untreated. Leishmaniasis is considered a major health problem with more than 1.5 million infections occurring each year, whereas current chemotherapy has important limitations including high toxicity and emergence of drug resistance. Thus, there is an urgent need to discover new drugs. For contributing to the fight against leishmaniasis the first research axis of the group investigates the pathogen and host signal transduction pathways, aiming to expand the drug-discovery platforms for the treatment of the disease. In this context, we use molecular and cellular biology techniques and systems approaches, to focus on the druggable genome and more specifically on kinases of the host implicated in inflammation (i.e. GSK-3, DYRK) and on parasitic kinases implicated in parasite viability, virulence and differentiation (i.e. GSK-3, Aurora, DYRK). Aiming towards the discovery of new antiparasitic drugs we have developed target- and cell- based screening assays, and we evaluate the efficacy of selected drugs in vivo, in animal models of leishmaniasis. The second research axis involves epidemiological studies of strains isolated in South-Eastern Europe for understanding parasite factors that determine the clinical outcome of leishmaniasis and factors that contribute to drug resistance.
Α. Investigation of signal transduction pathways and of proteins involved in Leishmania cell-cycle progression, differentiation and virulence
To achieve our research objectives we use transgenic parasites, molecular and cellular biology techniques and systems approaches for investigating components and mechanisms of signal transduction pathways.
- The loss of virulence of histone H1 over-expressing Leishmania donovani parasites is directly associated with a reduction of HSP83 rate of translation. Alexandratos, J. Clos, M. Samiotaki, A. Efstathiou, G. Panayotou, K. Soteriadou, D. Smirlis. Mol. Microbiology. 2013 Jun;88(5):1015-31.
- Trypanosomatid apoptosis: ‘Apoptosis’ without the canonical regulators. D. Smirlis, K. Soteriadou. Virulence. 2011 May 1;2(3).
- Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death. D Smirlis, M. Duszenko, A. Jimenez-Ruiz, E. Scoulica, P. Bastien, N. Fasel, K. Soteriadou. Parasit Vectors. 2010 Nov 17;3:107. (Highly accessed)
- Leishmania donovani RAN-GTPase interacts at the nuclear rim with linker histone H1. D. Smirlis, H. Boleti, M. Gaitanou, M. Soto, K. Soteriadou. Biochem. J. 2009 Dec 10;424(3):367-74 9.
- Leishmania histone H1 over-expression delays parasite cell-cycle progression, parasites differentiation and reduces Leishmania infectivity in vivo. D. Smirlis, S. Bisti, E. Xingi, G. Konidou, M. Thiakaki, K. Soteriadou. Mol. Microbiology. 2006; 60(6): 1457-73
Β. Drug discovery efforts against leishmaniasis and trypanosomiasis and investigation of the mechanism of drug action
To achieve this objective we have developed medium throughput non-radioactive kinase assays for investigating the inhibitory potential of Leishmania kinases and we assess cell growth inhibition and mechanism of drug action (cell-cycle, mechanism of cell death). Finally we assess the toxicity of selected compounds and their in vivo efficacy in a murine model of leishmaniasis.
- Indirubin analogues inhibit Typanosoma brucei Glycogen Synthase Kinase 3 short and T. brucei growth.. Efstathiou A, Gaboriaud-Kolar N, Myrianthopoulos V, Vougogiannopoulou K, Subota I, Aicher S, Mikros E, Bastin P, Skaltsounis AL, Soteriadou K, Smirlis D. Antimicrob Agents Chemother 2019 Mar 25. pii: AAC.02065-18. doi: 10.1128/AAC.02065-18. [Epub ahead of print]
- Indirubin derivatives are potent and selective anti-Trypanosoma cruzi Efstathiou A, Meira CS, Gaboriaud-Kolar N, Bastos TM, Rocha VPC, Vougogiannopoulou K, Skaltsounis AL, Smirlis D, Soares MBP. Virulence. 2018;9(1):1658-1668. doi: 10.1080/21505594.2018.1532242. PMID: 30387370
- Selection of molecular targets for drug development against trypanosomatids. D. Smirlis& M.B.P. Soares. In Proteins and Proteomics of Leishmania and Trypanosoma, Springer (Editor: dos Santos, A.L.S), Subcell Biochem. 2014;74:43-76. doi: 10.1007/978-94-007-7305-9_2. (Book Chapter)
- 5-Me-6-BIO targeting the leishmanial short form affects cell-cycle progression and induces apoptosis like death: exploitation of GSK-3 for treating leishmaniasis. E. Xingi, D. Smirlis, V. Myrianthopoulos, P. Magiatis, K. M. Grant, L. Meijer, E. Mikros, A. -L. Skaltsounis, K. Soteriadou. Int. J. Parasitol. 2009;39(12):1289-303
- In vitro activity of 10-deacetylbaccatin-III against Leshmania donovani promastigotes and intracellular amastigotes. K. Georgopoulou, D. Smirlis, S. Bisti, E. Xingi, L. Skaltsounis, K. Soteriadou. Planta Medica 2007 Aug;73(10):1081-8. Epub 2007 Aug 9
C. Epidemiological studies of strains isolated in South-Eastern Europe for understanding parasite factors that determine the clinical outcome of leishmaniasis and factors that contribute to drug resistance.
We use parasites MLMT typed that share the same genomic background to investigate distict phenotypes towards clinical outcome and drug resistance. By applying next generation sequencing or and other molecular biology approaches, we are trying to investigate on the mechanisms that contribute to the above phenotypes.
- Genetic diversity and structure in Leishmania infantum populations from south-eastern Europe revealed by microsatellite analysis. E. Gouzelou, C. Haralambous, M. Antoniou, V. Christodoulou, F. Martinković, T. Živičnjak , D. Smirlis, F. Pratlong, J.P. Dedet, Y. Özbel, S.Ö. Toz, W. Presber, G. Schönian, K. Soteriadou. Parasit Vectors. 2013 Dec 5;6:342.doi: 10.1186/1756-3305-6-342. (Highly accessed)
2016-2017: IKY: Scholarship of Excellence for post-doctoral studies Siemens, (Recipient: Dr Antonia Efstathiou)
2014-2017: International Pasteur Network: LeisHield: A new collaborative action to determine prevalence, anticipate emergence and assess urbanization of cutaneous and visceral leishmaniasis in LeishRIIP partner countries (Coordinator: Gerald Spath, PI: PI)
2013-2015: ACIP 2013 International Pasteur Network: “Evaluation of Leishmania DYRK family of kinases as molecular targets for the development of antileishmanial drugs” (Hellenic Pasteur Institute, IP Paris, IP Montevideo, FIOCRUZ) (Coordinator: Despina Smirlis)
2011-2015: FP7-PEOPLE-2010-IRSES: Exploring Chemical Biodiversity with Innovative Approaches for Fighting Chagas and Leishmaniasis. PIRCES-GA-2010-269301 (Coordinator: A.-L. Skaltsounis, PI: Ketty Soteriadou, Member, Co-PI: Despina Smirlis)
2012-2015: General Secretariat of Research and Technology KRIPIS: Infectious and neurodegenerative diseases of the 21st Century: From the study of basic mechanisms to translational research and development of cutting-edge technologies aiming towards prevention, diagnosis and treatment (WP leader), (WP Leader)
2011-2012: Foundation for Education and European Culture (IPEP) award: “Evaluation of the anti-leishmanial action of new indirubin analogues” (Recipient of Grant: Despina Smirlis)
Invited lectures/ Courses/ Seminars
- Research seminar of the Biology Department of the National Kapodistrian University of Athens: The unusual lives of trypanosomatids, 19-12-2012.
- UMR8638 CNRS-Université Paris Descartes, “Novel drug targets and drugs for the treatment of leishmaniasis, 19-7-2013.
- Institute Pasteur Paris, Scientific Symposium of the Institut Pasteur International Network “Exploring the role of Leishmania infantumDYRK1 and Aurora kinases in the parasitic lifecycle for anti-leishmanial drug discovery”, 11-9-14.
- Institut Pasteur, Tehran, Iran: International Workshop “Leishmania and leishmaniasis immunology, vaccine and drug discovery-therapy” Speaker: Recent approaches in anti-leishmanial drug discovery, 9-13 November 2016.
Theses/ Final Year Projects
2012-now: Currently co-supervising with Dr Milena Soares (FIOCRUZ, Bahia, Brazil) Mr. Vinicius Pinto Rocha
2017: Foteini Kolokousi Dissertation supervisor (Biology, NKUA) in the project entitled “Exploring the role of Leishmania infantum DYRK1 for antileishmanial drug discovery”
2016: Garyfallia Loulou Dissertation supervisor (Technical University of Athens) in project entitled “Phenotypic characterisation of Leishmania infantum parasites knocked out or over-expressing the Leishmania dual specificity tyrosine regulated kinase 1 (DYRK1), for the study of its biological role”
2010-2014: Co-supervisor of Antonia’s Efstathiou PhD thesis entitled (Biology, National Kapodistrian University of Athens) entitled «Study of molecules implicated in the development of Leishmania and T.brucei parasites»
2010-2013: Co-supervisor of Alexandros Alexandratos PhD thesis (Chemistry, University of Ioannina) “Study of molecules important for cell-cycle progression in the protozoan parasite Leishmania”
2009: Evangelos Nomikos BSc Final Year Project Supervisor (Technical University of Athens) in the final Year Project entitled “Expression and purification of a Leishmania RCC1 protein fragment”
2008: Irene’s Daoudadakis BSc Final Year Project Supervisor (Technical University of Athens) in a project entitled “Construction of targeted cassettes for the knockout of Leishmania protein Ran”
2007-2008: Anastasios Katopodis Final Year (Biology, National Kapodistrian University) Project Supervisor in a project entitled “Cloning and molecular characterisation of the Leishmania protein Ran”
AWARDS - HONORS
1997-2001: Welcome Trust Toxicology PhD Prize Studentship
09/2009: Recipient of the Short Mission Fellowship of the COST BM0802 Action for training in theTrypanosome Cell BiologyLaboratory – CNRS URA 2581, Institute Pasteur Paris (Dr P. Bastin)
2009-2012: Appointed Greek Management Committee substitute member of the BM0802 action- Life or death of protozoan parasites
4-8/2013: Recipient of the Programme Calmette and Yersin traineeship (International Pasteur Network) in the Molecular Parasitology and Signaling Unit of Institut Pasteur: “Generation of conditional Leishmhania Aurora null mutants for investigating the role of this kinase in the parasitic life-cycle and evaluating its potential as a putative drug target for anti-leishmanial chemotherapy”
2013-2015: Coordinator of Actions Concertées des Institut Pasteur (ACIP, 2013)
2015-2017: Appointed Greek Management Committee Substitute Member for Greece in the COST CM1307 ACTION “Targeted chemotherapy towards diseases caused by endoparasites”
9-12/2015: Recipient of the Short Mission Fellowship of the COST CM1307 Action “Investigating regulatory& functional elements of Leishmania infantum Aurora kinase, and assessment of its role in parasite genomic adaptation”in the Molecular Parasitology and Signaling Unit of Institut Pasteur
11-02-2016: Unesco-Hellas Award for Scientific achievement
- Κείμενο 01
- Κείμενο 02
- Κείμενο 01
- Κείμενο 02
Giraud E, Rouault E, Fiette L, Colle JH, Smirlis D, Melanitou E. Osteopontin in the host response to Leishmania amazonensis. BMC Microbiol. 2019 Feb 8;19(1):32. doi: 10.1186/s12866-019-1404-z.PMID: 30736736 Free PMC Article
Hombach-Barrigah A, Bartsch K, Smirlis D, Rosenqvist H, MacDonald A, Dingli F, Loew D, Späth GF, Rachidi N, Wiese M, Clos J. Leishmania donovani 90 kD Heat Shock Protein - Impact of Phosphosites on Parasite Fitness, Infectivity and Casein Kinase Affinity. Sci Rep. 2019 Mar 25;9(1):5074. doi: 10.1038/s41598-019-41640-0
Efstathiou A, Gaboriaud-Kolar N, Myrianthopoulos V, Vougogiannopoulou K, Subota I, Aicher S, Mikros E, Bastin P, Skaltsounis AL, Soteriadou K, Smirlis D. Indirubin analogues inhibit Trypanosoma brucei Glycogen Synthase Kinase 3 short and T. brucei growth. Antimicrob Agents Chemother. 2019 Mar 25. pii: AAC.02065-18. doi: 10.1128/AAC.02065-18. [Epub ahead of print]
Efstathiou A, Meira CS, Gaboriaud-Kolar N, Bastos TM, Rocha VPC, Vougogiannopoulou K, Skaltsounis AL, Smirlis D, Soares MBP. Indirubin derivatives are potent and selective anti-Trypanosoma cruzi agents. Virulence. 2018;9(1):1658-1668. doi: 10.1080/21505594.2018.1532242.
Agallou M, Pantazi E, Tsiftsaki E, Toubanaki DK, Gaitanaki C, Smirlis D, Karagouni E. Induction of protective cellular immune responses against experimental visceral leishmaniasis mediated by dendritic cells pulsed with the N-terminal domain of Leishmania infantum elongation factor-2 and CpG oligodeoxynucleotides. Mol Immunol. 2018 Nov;103:7-20. oi: 10.1016/j.molimm.2018.08.004
Bussotti G, Gouzelou E, Côrtes Boité M, Kherachi I, Harrat Z, Eddaikra N, Mottram JC, Antoniou M, Christodoulou V, Bali A, Guerfali FZ, Laouini D, Mukhtar M, Dumetz F, Dujardin JC, Smirlis D, Lechat P, Pescher P, El Hamouchi A, Lemrani M, Chicharro C, Llanes-Acevedo IP, Botana L, Cruz I, Moreno J, Jeddi F, Aoun K, Bouratbine A, Cupolillo E, Späth GF. Leishmania Genome Dynamics during Environmental Adaptation Reveal Strain-Specific Differences in Gene Copy Number Variation, Karyotype Instability, and Telomeric Amplification. MBio. 2018 Nov 6;9(6). pii: e01399-18. doi: 10.1128/mBio.01399-18.
G. Zoidis, A. Tsotinis, A. Tsatsaroni, M.C. Taylor, J.M. Kelly, A. Efstathiou, D. Smirlis, G. Fytas. Lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine-1-acetohydroxamic acid analogues as trypanocidal and leishmanicidal agents: An extended SAR study. Chem Biol Drug Des. (2017) Aug 21. doi: 10.1111/cbdd.13088. [Epub ahead of print]
G.B.B. Njock, R. Grougnet, A. Efstathiou, D. Smirlis, G. Genta-Jouve, S Michel, J.N. Mbing, M. Kritsanida. A Nitrile Glucoside and Biflavones from the Leaves of Campylospermum excavatum (Ochnaceae). Chem Biodivers. 2017 Nov;14(11). doi: 10.1002/cbdv.201700241. Epub 2017 Oct 21.
I. D. Kyriazis, D. Smirlis, A. Papadaki, O. Koutsoni, N. Aligiannis, A-L Skaltsounis. E. Dotsika (2017) Leishmanicidal Activity of Oleuropein: Leishmania donovani Promastigote Cell Death through a Possibly ROS-Independent Mechanism. J Pharmacogn Nat Prod 3: 141. doi: 10.4172/2472-0992.1000141
Azevedo L, Faqueti L, Kritsanida M, Efstathiou A, Smirlis D, Franchi GC Jr, Genta-Jouve G, Michel S, Sandjo LP, Grougnet R, Biavatti MW. Three new trixane glycosides obtained from the leaves of Jungiasel lowii Less. using centrifugal partition chromatography. Beilstein J Org Chem. (2016) Apr 12;12:674-83. doi: 10.3762/bjoc.12.68. eCollection 20162016
A. Papadaki, A.S. Politou, D. Smirlis, M.P. Kotini, K. Kourou, T. Papamarcaki, H. Boleti.The Leishmania donovani histidine acid ecto-phosphatase LdMAcP: insight into its structure and function. Biochem J. (2015) May 1;467(3):473-86. doi: 10.1042/BJ20141371. (1 citation)
M. Becerra, S. Boutefnouchet, O. Cordoba, L. Brehuc, I. Lamour, F. Laimay,A. Efstathiou, D. Smirlis, S. Michel, M. Kritsanida, M.L. Flores, R. Grougnet. Antileishmanial activity of fucosterol recovered from lessonia vadosa by SFE, PSE and CPC Phytochem Letters; March 2015; 11: 418–423;doi:10.1016/j.phytol.2014.12.019
D. Stellas, V.L. Souliotis, M. Bekyrou, D. Smirlis, M. Kirsch-Volders, F. Degrassi, E. Cundaric, S. A. Kyrtopoulos. Benzo[a]pyrene-induced cell cycle arrest in HepG2 cells is associated with delayed induction of mitotic instability(2014) Mut Res/Fundamental and Molecular Mechanisms of Mutagenesis 11/2014; 769:59–68
A. Efstathiou, N. Gaboriaud-Kolar, D. Smirlis, V. Myrianthopoulos, K.Vougogiannopoulou, A.Alexandratos, M. Kritsanida, E. Mikros, K. Soteriadou, A.-L.Skaltsounis. An inhibitor-driven study for enhancing the selectivity of indirubin derivatives towards leishmanial Glycogen Synthase Kinase-3 over leishmanial cdc2-related protein kinase-3. Parasit Vectors. 2014 May 20;7:234. doi: 10.1186/1756-3305-7-234 (Highly accessed)
D. Smirlis* & M.B.P. Soares. Selection of molecular targets for drug development against trypanosomatids. In Proteins and Proteomics of Leishmania and Trypanosoma, Springer (Editor: dos Santos, A.L.S), Sub cell Biochem. 2014;74:43-76. doi: 10.1007/978-94-007-7305-9_2. (Book Chapter)
E.Gouzelou, C. Haralambous, M. Antoniou, V. Christodoulou, F. Martinković, T. Živičnjak , D. Smirlis, F. Pratlong, J.P. Dedet, Y. Özbel, S.Ö. Toz, W. Presber, G. Schönian, K. Soteriadou.Genetic diversity and structure in Leishmaniainfantum populations from southeastern Europe revealed by microsatellite analysis.Parasit Vectors. 2013 Dec 5;6:342. doi: 10.1186/1756-3305-6-342. (Highly accessed)
L. Sacconnay, D. Smirlis, E. F. Queiroz,J. L. Wolfender, M. B. P. Soares, P. A. Carruptand A. Nurisso Structural insights of SIR2rp3 proteins as promising biotargets to fight against Chagas disease and Leishmaniasis, MolBiosyst. 2013 Sep;9(9):2223-30
A. Alexandratos, J. Clos, M. Samiotaki, A. Efstathiou, G. Panayotou, K. Soteriadou, D.Smirlis*.The loss of virulence of histone H1 over-expressing Leishmania donovani parasites is directly associated with a reduction of HSP83 rate of translation. Mol. Microbiology.2013 Jun;88(5):1015-31.
N. Vassilaki, K. Kalliampakou, I. Kotta-Loizou, C. Befani, P. Liakos, G. Simos, A. Mentis, A. Kalliaropoulos, P. Doumba, P. Foka, D. Smirlis, O. Bauhofer, M. Poenisch, M.Windisch, M. Eun Lee, J. Koskinas, R. Bartenschlager, and P. Mavromara.Low Oxygen Tension Enhances Hepatitis C Virus Replication. Journa of Virology. 2013 Mar;87(5):2935-48. doi: 10.1128/JVI.02534-12
M. Agallou, D. Smirlis, K.P. Soteriadou, E. Karagouni. Vaccination with Leishmania histone H1-pulsed dendritic cells confers protection in murine visceral leishmaniasis. Vaccine. 2012 Jul 20;30(34):5086-93. Epub 2012 Jun 13
M.B.P.Soares, C.V. Silva, T.M. Bastos, E.T. Guimarães, C.P. Figueira, D. Smirlis, Azevedo WF Jr. Antitrypanosomal activity of nicotinamide. Acta Tropica. 2012 May;122 (2):224-9. doi: 10.1016/j.actatropica.2012.01.001
D. Smirlis*, K. Soteriadou. Trypanosomatid apoptosis: 'Apoptosis' without the canonical regulators.Virulence. 2011 May 1;2(3)2011
D Smirlis*, M. Duszenko, A. Jimenez-Ruiz , E. Scoulica, P. Bastien, N. Fasel, K. Soteriadou Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death. Parasit Vectors. 2010 Nov 17;3:107. (Highly accessed)
H. Boleti*, D. Smirlis, S. Christoforidis, G. Dalagiorgou, E. Meurs, P. Mavromara.The HCV NS4B protein contains multiple signals for association with the ER membrane while its transmembrane domains are responsible for ER retention. Mol Membr Biol. 2010 Jan;27(1):50-74
D. Smirlis*, H. Boleti, M. Gaitanou, M. Soto, K. Soteriadou.Leishmania donovani RAN-GTPase interacts at the nuclear rim with linker histone H1.Biochem. J.2009 Dec 10;424(3):367-74 9.
E. Xingi, D. Smirlis, V. Myrianthopoulos, P. Magiatis, Karen M. Grant, Laurent Meijer, Emmanuel Mikros, A.-L. Skaltsounis and K. Soteriadou. 5-Me-6-BIO targeting the leishmanial short form affects cell-cycle progression and induces apoptosis like death: exploitation of GSK-3 for treating Leishmaniasis. Int. J. Parasitol. 2009;39(12):1289-303
K. Georgopoulou, D. Smirlis, S. Bisti, E. Xingi, L. Skaltsounis, K. Soteriadou. In vitro activity of 10-deacetylbaccatin-III against Leshmania donovani promastigotes and intracellular amastigotes. Planta Medica2007 Aug;73(10):1081-8. Epub 2007 Aug 92007
D. Smirlis, S. Bisti, E. Xingi, G. Konidou, M. Thiakaki, K. Soteriadou. Leishmania histone H1 over-expression delays parasite cell-cycle progression, parasite differentiation and reduces Leishmania infectivity in vivo. Mol. Microbiology2006; 60(6): 1457-73
Edwards M, Wong SC, Chotpadiwetkul R, Smirlis D, Phillips R, Shephard EA*.Transfection of primary cultures of rat hepatocytes. Methods Mol Biol. 2006;320:273-82. (Book Chapter)
Muangmoonchai R, Wong SC, Smirlis D, Phillips IR, Shephard EA*. Transfection of liver in vivo by biolistic particle delivery: its use in the investigation of cytochrome P450 gene regulation Mol Biotechnol. 2002 Feb;20(2):145-512002
R. Muangmoonchai, D. Smirlis, S.C. Wong, M. Edwards, I.R. Phillips, E.A. Shephard* Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1. Biochem J. 2001 Apr 1;355(Pt 1):71-8.
D. Smirlis, R. Muangmoonchai, M. Edwards, I.R. Phillips, E.A. Shephard*. Orphan receptor promiscuity in the induction of cytochromes p450 by xenobiotics. J Biol Chem. 2001 Apr 20;276(16):12822-6. Epub 2001 Jan 24.