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Centre d'Immunologie et des Maladies Infectieuses
UPMC UMRS CR7 - Inserm U1135 - CNRS ERL 8255

Malaria: identification and pre-clinical validation of novel therapeutics - Dominique MAZIER

Team members

Team Research Program

The hepatic stages of Plasmodium parasites.

Our team is principally devoted to investigations on the biology and the immunology of the hepatic stages of the human Plasmodium parasites. A fraction of the parasites in the liver, called hypnozoites, can remain "dormant" a year or more, before waking up over time, causing a blood infection.
This liver stage of parasite development, specific for P. vivax and P. ovale species of malaria, represents a double challenge for malaria elimination and poses a considerable health problem, as it increases both a greater number of patients to be treated and the intensity of transmission.
Unfortunately, primaquine (and its recently developed equivalent tafenoquine), the only drugs that specifically kill the hypnozoites have side effects, sometimes severe for the patients.

Different models developed in the laboratory in vitro (primary human and simian hepatocytes) and in vivo (humanized or simianized mice), cell penetrating peptides, allow us to work on the phenomena of quiescence / reactivation of hypnozoites both for a better understanding of this biological phenomenon, and also for identifying  new drugs / strategies that could lead to radical cure, innovative and non-toxic.

Technical expertise

Our principal asset is an expertise in the in vitro cultivation of hepatic parasites in their natural host cell, the hepatocyte, in particular in human primary hepatocytes, and over the last years in those of Macaca species. In addition to the usual rodent malaria species, we regularly cultivate the liver forms of P. falciparum, P. vivax, P. ovale and P. cynomolgi. We have recently succeeded in cultivating the hypnozoites, the dormant forms responsible for relapse infections, of these last three species, and we have added liver-humanized/simianized immune-deficient mice to our repertoire of laboratory-based models.

Main achievements

  • Establishment of a number of in vitro and in vivo models to investigate pre-erythrocytic stages of  human malaria parasites (Nature 1984, Science 1985, PLoS ONE 2009)
  • Demonstration of the role of antibodies, CD4+, CD8+ T lymphocytes cytotoxicity, ADCC mechanisms in protection against malaria pre-erythrocytic stages (Science 1986, PNAS 1991)
  • Identification of host molecules that are crucial for penetration/development of sporozoites (CD81, SRB1) (Nature Medicine 2003, Cell Host Microbe, 2008)
  • Discovery of an inhibitor of histone methyltransferases capable of accelerating the rate of hypnozoite activation. Proposition of a novel strategy, “wake & kill” to eliminate hypnozoites, based on the fact that unlike hypnozoites, dividing hepatic parasites are inhibited to some current antimalarials. We seek to validate pre-clinically a combination therapy in which the hypnozoites are woken up to initiate maturation, thus becoming susceptible to elimination by a companion drug  (Nat Med, 2014)
  • Using Laser capture microdissection (LCM) coupled to RNA-seq, we recently contrasted the transcriptome of hypnozoites versus that of dividing forms. This allowed us to identify genes that are overexpressed in the hypnozoite and are therefore potentially involved in the maintenance of the quiescent state of hypnozoites (Cellular Microbiology, 2017).

External funding (current)

FP7 projects:

  • 2017-2022: OptiMalVax “Optimizing a deployable high efficacy malaria vaccine”
  • 2014-2016 : M3S-2S : Molecular signature Detection with multi-modal microscopy scanner
  • 2012-2017 : Pathco "Pathogen Co-infection: HIV-1, Tuberculosis, Malaria and Hepatitis C virus"
  • 2012-2017 : MultiMalVax "A multistage Malaria Vaccine"

ANR:

  • 2018-2021: “Investigations on the Malaria Hypnozoite”
  • 2014-2018 : “Developing a wake and kill radical cure strategy by exploring the epigenetic control of the quiescence of the malaria hypnozoite”.
  • 2010-2014 : « Mechanisms of action and targets of new antimalarial redox molecules »
  • 2010-2011 : « Développement de candidats vaccins particulaires par les voies « transcutanée » et intradermique dans un modèle murin-humanisé : exemple d’antigènes de Plasmodium falciparum ».
  • 2006-2010 : « Evaluation du potentiel de valorisation d’une nouvelle tête de série spécifiquement active sur les stades hépatiques des Plasmodium »
    2006-2010 : “Dynamics, assembly and function of tetraspanin-enriched microdomains”

Conectus:

2010-2011 : New Polysphorin Analogs Identified as HITS for the Development of Anti-malaria Drugs


FRM:

  • 2015-2017: « Projets Innovants » : « Targeting the liver stage of human malaria parasites : new preclinical models for chemotherapeutic and immunoprophylactic interventions »
  • 2013-2015: “Antimalarial drugs targeting the mitochondrion – Revisiting old drugs and finding novel leads”
  • 2013-2014 : « Antimalaria drugs targeting the mitochondrion – revisiting old drugs and finding novel leads »
  • LABEX Network of excellence
  • 2012-2020 : " ParaFrap "

DIM:

  • 2013-2014 : « Resistance of hepatic forms to atovaquone-proquanil ». Co-investigateur
  • 2013-2014 : « Investigations on the mechanisms of quiescence in the hypnozoites of the malaria parasite Plasmodium vivax »
    Wellcom Trust/MMV:
  • 2009-2011 : Towards an in vitro liver-stage assay to enable drug discovery of new antimalarial drugs for the treatment of P. vivax malaria”

Publications (PDF):

(2017 - 2016 - 2015 - 2014 - 2013)

23/10/17

Traductions :

Contact

cimi-paris @ upmc.fr

To see

Key words

Pre-erythrocytic stages of human malaria, hypnozoite, vaccination, human/simian hepatocytes, drugs, cerebral malaria

Fields of application

Pre-erythrocytic malaria vaccines,treatment against malaria, Radical cure (against hypnozoite)