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    The mode of action of artemisinines : Fédéric Ariey, MD-PhD. Institut Pasteur.

    FrédéricAriey



     

     

     

     

        Artemisinin-based combination therapies (ACTs) are the mainstay of treatment for P. falciparum malaria in Sub-Saharan Africa, but resistance to artemisinin has emerged on the Thai-Cambodian border and most probably in other sites independently and is now spreading to neighbouring countries areas. We recently identified the ‘K13-propeller’ as a key determinant of delayed parasitological clearance after artemisinin treatment, showing that single nucleotide polymorphisms (SNPs) in the gene are associated with resistance both in vitro and in vivo (1).
        Based on sequence homology, we modelled the 3D structure of the Kelch domain of the K13 gene that is directly involved in resistance to artemisinins and we think that the mutations destabilize the structure or alter surface charges and therefore the function this kelch domain. It should be noted the similarity of this gene with several human proteins, including KLHL1 and KLHL2, proteins involved in protein degradation (ubiquitin family) and KEAP1, involved in cellular adaptation to oxidative stress. As part of the response to artemisinin, which mainly depends on its antioxidant activity, the well-established role of these proteins in regulating the cytotoxic response protective after exposure to oxidative stress is particularly relevant. These data are put in parallel with studies showing the activation of the KEAP1/NFR2 response when using artesunate in models of oxidative diseases in mice, or in human cells in culture.
        The mode of action of artemisinins remains highly controversial. However, it is assumed that its activity is increased by haemoglobin digestion and iron release. However, we know neither the mode of penetration, nor the target, nor even how the parasite dies (probably by oxidative stress but then apoptosis, autophagy, others?).
        Our project will be built on our expertise in exploring metabolic pathways of P. falciparum to understand the response of the parasite to oxidative stress induced by artemisinins by analysis coupled transcritpome / metabolome / lipidome and functional explorations of oxidative level of red blood cells.
    In parallel we will explore the consequences of treatment with artesunate of other apicomplexans (Theileria & Toxoplasma) and human cells in culture to assess the involvement of KEAP1/NRF2 regulation in the mode of action of artemisinins.

        Finally, through a comparison between wild type and mutant parasites, we will explore the mechanisms behind the death of P. falciparum induced by artemisinins (apoptosis, autophagy , ..) and try to propose new avenues of research for identification of new drug target candidates.

    1) A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.
    Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S, Suon S, Chuor CM, Bout DM, Ménard S, Rogers WO, Genton B, Fandeur T, Miotto O, Ringwald P, Le Bras J, Berry A, Barale JC, Fairhurst RM, Benoit-Vical F, Mercereau-Puijalon O, Ménard D.
    Nature. 2014 Jan 2;505(7481):50-5.

     

    INTERNATIONAL

     Dirk Werling

    Molecular Immunology Group, 

    Department of Pathology and Pathogen Biology, 

    Royal Veterinary College, Hawkshead Lane, Hatfield AL9 7TA, UK.

                  

    Amitabha Mukhopadhyay

    National Institute of Immunology,
    Aruna asaf Ali Marg,
    New Delhi 110067