All host/pathogen interactions rely on a constant co-evolutionary battle between genetically highly diverse microbial populations that infect equally diverse human or animal populations, with fitness gains selected both in pathogen and host through complex genotype-genotype interactions. The protozoan parasite Leishmania perfectly well illustrates this genetic cross-talk, with frequent phenotypic shifts (in pathogenicity, drug susceptibility or tissue tropism) selected in Leishmania field isolates through interactions with their heterogeneous vertebrate hosts, which in return react with very diverse clinical responses ranging from asymptomatic infection to fatal immunopathology. Despite the relevance of this highly dynamic host/pathogen relationship for disease outcome and parasite evolution, its underlying molecular mechanisms and physiological consequences remain poorly understood. To address these open questions, our team has initiated over recent years an important thematic transition from its past focus on molecular analysis of parasite signaling to its current and future focus on systems level analysis of Leishmania/macrophage interaction. This new focus animates the projects of three sub-teams that investigate (i) mechanisms of Leishmania evolutionary adaptation and fitness gain at genomic, transcriptomic and translational levels in culture, in animals (sand fly and hamster) and clinical infection (Axis 1), (ii) how Leishmania interferes in trans with macrophage functions through the exosomal release of parasite signaling proteins (Axis 2), and (iii) how Leishmania subverts macrophage immuno-metabolic functions on epigenetic and transcriptional levels to establish permissive conditions for intracellular infection (Axis 3).
Signalling and host-parasite interactions
PostDocs: Suzanne Lamotte (2018 – 2019), Sima Drini (2016 – 2017), Penny Smirlis (2015 – 2017), Mathieu Cayla (2014 – 2015), Mariko Dacher (2012 -2014), Najma Rachidi (2011 – 2015), Wai-Lok Yau (2011 – 2012), Dirk Schmidt-Arras (2007 – 2010), Claire Forestier (2005 – 2008), Miguel Morales (2003 – 2011)
PhD students: Director/co-Director of thesis: Laura Piel (2015 – 2020), Daniel Martel (2015 – 2019), Suzanne Lamotte (2014 – 2018), Sima Drini (2012 – 2016), Mathieu Cayla (2010 – 2014), Mariko Dacher (2008 -2012), Wai-Lok Yau (2009 – 2012)
M2 students: Thibault Rosazza (2018/19), Marie Ajavon (2018), Candide Dossa (2018), Adrien Blisnick (2014), Franck Dumetz (2012), Amel Abdelkarim (2010)
Trainees: Ihcen Kheraci, IP Algers (RIIP* fellow, 3 months 2019); Rafik Garni (RIIP* fellow, 3 months 2019); Arezou Lari, IP Iran (RIIP fellow, 3 months 2019); Farideh Bahari, IP Iran (RIIP* fellow, 3 months 2019); Mariana Boté-Cortes, Fiocruz Brazil (RIIP* visiting fellow, 3 months in 2017); Kyungwa Baek, IP Korea (RIIP fellow, 3 months, 2017); Kossiwa Kokou, IPShanghai (RIIP fellow, 3 months 2016); Evi Gouzelou, Hellenic Pasteur Institute (RIIP trainee, 4 months, 2015); Penny Smirlis, Hellenic Pasteur Institute (EU COST fellow, 1 month, 2015); Joo Hwan No, IP Korea (RIIP fellow, 1 month, 2014); Aymen Bali, (RIIP visiting fellow, 4 months, 2014); Penny Smirlis, Hellenic Pasteur Institute (RIIP trainee, 4 months, 2013); Grace Tewkesbury, Duke University (summer intern Pasteur Foundation, 2 months, 2013); Naouel Eddaikra, IP Alger (RIIP trainee, 1 month, 2013); Monica Gardner, IP Montevideo (RIIP trainee, 2 months, 2012); Sofia Horjales, IP Montevideo (RIIP trainee, 1 month, 2012); Stewart Pine, Harvard University (summer intern, 2 months, 2012); Samin Houshyar, MIT (summer intern, 2 months, 2011); Analia Lima, IP Montevideo (RIIP trainee, 3 months, 2011); Juan-Roman Luque-Ortega, CSIC Madrid (EMBO fellow, 2010); Sylvane Murta, Fiocruz Brazil, (RIIP fellow, 4 months, 2010); Nathalie Joli (summer intern, 1 month, 2010); Najiha Bilal Farooqi (International Fellow, Aga Khan University Medical College, Karachi, Pakistan, 2 months, 2010); Fatma Guerfali, IP Tunis (RIIP trainee, 3 months in 2009); Tahereh Taheri, IP Iran (RIIP trainee, 3 months, 2008), Elahe Davarpanah, IP Iran (RIIP trainee, 3 months in 2022), Ikram Maatallah, IP Morocco (RIIP trainee, 3 months in 2022)
“Modelling and functional analysis of clonal Evolution in Leishmania – possible role of non-coding RNAs and RNA modification”
Recipient: Gerald Spaeth, coordinator Agency: Campus France, MEAE, Type: Bi-national program France/Israel, 04/2018 – 03/2020 Leishmaniasis is among the five most serious parasitic diseases worldwide. The cutaneous form of the disease is prevalent in […]
H2020-MSA-RISE-2017: LeiSHield-MATI consortium
LeiSHield-MATI forms an international, inter- and multidisciplinary consortium that aims to gain scientific knowledge on parasite-vector-host interaction to allow future development of new therapeutic and preventive measures through research and innovation staff exchange and […]
ANR Patho-Methylome – The role of lysine methylation in host-pathogen interactions
The interaction between two eukaryotic genomes provides a fascinating example of co-evolution of host-parasite interactions. Two genomes, two epigenomes, two cellular systems living together. Our proposal focuses on the fascinating features of the interaction […]
International Mixed Unit ‘Inflammation and Leishmania infection’ (IMU-InflaLeish): Exploiting host-pathogen interaction for the discovery of novel anti-microbial drug targets and drug candidates.
Recipient: Gerald Spaeth, PI Agency: Pasteur Institute, Type: Collaborative grant, 01/2016 – 12/2019 Based on ongoing collaborative actions we propose the creation of an IMU between three teams at IP Paris (G. Spaeth), IP […]
PTR 539 – A multilevel systems approach to elucidate the host-Leishmania interactome and to identify host targets for anti-leishmanial drug discovery
Our PTR project investigates at the complex interface between the intracellular pathogen Leishmania and its macrophage host cell. We will apply systems-wide analyses to elucidate the molecular mechanisms underlying the reciprocal metabolic relationship between […]
PTR 496 – Investigating the reciprocal relationship between macrophage inflammasome activity and intracellular Leishmania infection
Our proposal aims to decipher novel subversion strategies used by Leishmania (i) to withstand, circumvent or inhibit anti-microbial activities of host macrophages and (ii) to interfere with the induction of Leishmania-specific immune responses. We […]
ANR TranSig – Trans-signalling: A novel mechanism of Leishmania host cell immune evasion through the release of parasite signalling proteins
Intracellular parasitism is a major hallmark of the most successful and deadly human pathogens. This microbial survival strategy is especially devastating if immune cells are exploited as hosts. Here we propose to use the […]
LeiSHield – A new collaborative action to determine prevalence, anticipate emergence and assess urbanization of cutaneous and visceral leishmaniasis in LeishRIIP partner countries
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 […]
FP7 Anti-Parasitic Drug Discovery in Epigenetics (A-ParaDDisE)
We will employ a target-based strategy for the development of novel drug leads against epigenetic targets in schistosomiasis, leishmaniasis, Chagas disease and malariafocusing on key histone modifying enzymes (HME), in particular those involved in […]
ANR TransLeish – Discovery of druggable protein kinases in the protozoan parasite Leishmania donovani using hit compounds identified by phenotypic screening
The protozoan parasite Leishmania donovani causes fatal visceral leishmaniasis, one of the most neglected tropical diseases. In the absence of economic incentive, serious Research and Development (R&D) investments into anti-leishmanial drug development lack from […]
PTR 392 – Systems-wide analysis of Leishmania virulence
This PTR aims to gain novel insight into the nature, the expression, and the regulation of Leishmania virulence factors through the investigation of genetics, transcriptomics, and proteomics differences between (i) virulent and avirulent L. […]
FP7 Targeting the Leishmania kinome for the development of novel anti-parasitic strategies (LeishDrug)
Visceral leishmaniasis is caused by the protozoan parasites Leishmania donovani and Leishmania infantum and is a potentially fatal disease in endemic areas around the world. During the infectious cycle, Leishmania alternate between the insect […]
ANR ELATION: Epigenetic subversion in Leishmania macrophage infection
Gerald Spaeth, coordinator and PI Eric Prina, co-PI Manfred Jung (University of Freiburg, Germany), collaborator Dysregulation of epigenetic control has been recognized as a major source of human disease, ranging from cancer to microbial […]
Campus France – Franco-Thai Mobility Programme / PHC SIAM. Comparative genomic analysis and phenotypic drug screening of Leishmania martiniquensis and Leishmania orientalis, the parasites causing emerging leishmaniasis in Thailand.
Gerald Spaeth, PI and co-coordinator Narissara Jariyapan (Chulalongkorn University, Bangkok, Thailand), PI and co-coordinator Leishmaniasis in humans is caused by at least 21 species of Leishmania parasites via sand fly bites. Infection results in […]
Campus France – PRIX « TREMPLIN » DE COOPERATION BILATERALE EN RECHERCHE – AFRIQUE : Génomique comparative pour l’étude de l’épidémiologie et de l’expression clinique des leishmanioses causées par Leishmania infantum en Tunisie.
Gerald Spaeth, PI and co-coordinator Aida Bouratbine (IP Tunis), PI and co-coordinator Les pathologies cutanées et viscérales causées par Leishmania infantum représentent un problème majeur de santé publique dans tous les pays du Maghreb […]
PTR 425 EvoLeish: Mapping mechanisms of evolutionary adaptation underlying fitness gain in New World L. infantum strains
Gerald Spaeth, PI Pascale Pescher, co-PI Mariana Boité (Fiocruz Rio de Janeiro, Brazil), coordinator American Visceral Leishmaniasis (AVL) is a persistent public health challenge in the Americas, representing one of the main failures of […]
Emerging Infectious Diseases
Ever since its very early days, the Institut Pasteur has been committed to tackling emerging infections, and its work has left an extraordinary legacy. Many emerging infectious diseases are zoonoses, in which an animal […]
Antimicrobial resistance is dramatically increasing worldwide and is becoming one of the most urgent public health threats. There is an urgent need for actions to reverse the curve of antimicrobial resistance dissemination and to […]
INCEPTION – Institut Convergence for the study of Emergence of Pathology Through Individuals and Populations
IINCEPTION Goal The Inception’s goal is to develop a core structure to mobilize data resources, numerical sciences, and fundamental experimental biology in a range of health issues (Official website here : https://www.inception-program.fr/en). Inception program […]
The institut Carnot Pasteur MS
Carnot, label of excellence Founded in 2006, the Carnot Label, granted by the French government, was designed to develop partnership-based research, meaning research conducted by public laboratories in partnership with socio-economic players, primarily industry […]
LabEx IBEID – Integrative Biology of Emerging Infectious Diseases
Presentation The aim of the Integrative Biology of Emerging Infectious Diseases (IBEID) project, coordinated by Professors Philippe Sansonetti and Pascale Cossart, is to develop a structure to anticipate and tackle emerging infectious diseases (EIDs). […]
2022Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni., ACS Infect Dis 2022 Jun; (): .
2022Experimental evolution links post-transcriptional regulation to Leishmania fitness gain., PLoS Pathog 2022 Mar; 18(3): e1010375.
2021Genome instability drives epistatic adaptation in the human pathogen Leishmania., Proc Natl Acad Sci U S A 2021 12; 118(51): .
2021GIP: an open-source computational pipeline for mapping genomic instability from protists to cancer cells., Nucleic Acids Res 2021 Dec; (): .
2021Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells., Immunity 2021 12; 54(12): 2724-2739.e10.
2021Going ballistic: Leishmania nuclear subversion of host cell plasticity., Trends Parasitol 2021 Oct; (): .
2021Cutaneous Leishmaniasis in Algeria; Highlight on the Focus of M’Sila., Microorganisms 2021 Apr; 9(5): .
2021Colonization and genetic diversification processes of Leishmania infantum in the Americas., Commun Biol 2021 01; 4(1): 139.
2021In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition., Eur J Med Chem 2021 Jan; 210(): 112956.
2021Identification of the Host Substratome of Leishmania-Secreted Casein Kinase 1 Using a SILAC-Based Quantitative Mass Spectrometry Assay., Front Cell Dev Biol 2021 ; 9(): 800098.
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