Leishmania; mucocutaneous leishmaniasis; Leishmania RNA virus; immune response; anti-leishmania drugs
Bourrerau E et al. and Fasel N (2016), Leishmania-RNA virus presence in L.guyanensis parasites increases the risk of first-line treatment failure and symptomatic relapse, in Journal of Infectious Diseases
Casanova M et al and Fasel N (2015), Implication of different domains of the Leishmania major metacaspase in cell death and autophagy, in Cell Death Disease
, 6(October), 288.
Ashok Devika, Schuster Steffen, Ronet Catherine, Rosa Muriel, Mack Vanessa, Lavanchy Christine, Marraco Silvia F, Fasel Nicolas, Murphy Kenneth M, Tacchini-Cottier Fabienne, Acha-Orbea Hans (2014), Cross-presenting dendritic cells are required for control of Leishmania major infection., in European journal of immunology
Zangger Haroun, Hailu Asrat, Desponds Chantal, Lye Lon-Fye, Akopyants Natalia S., Dobson Deborah E., Ronet Catherine, Ghalib Hashim, Beverley Stephen M., Fasel Nicolas (2014), Leishmania aethiopica Field Isolates Bearing an Endosymbiontic dsRNA Virus Induce Pro-inflammatory Cytokine Response, in PLoS Neglected Tropical Diseases
, 8(4), e2836-e2836.
Ives Annette, Masina Slavica, Castiglioni Patrik, Prével Florence, Revaz-Breton Mélanie, Hartley Mary-Anne, Launois Pascal, Fasel Nicolas, Ronet Catherine (2014), MyD88 and TLR9 Dependent Immune Responses Mediate Resistance to Leishmania guyanensis Infections, Irrespective of Leishmania RNA Virus Burden, in PLoS ONE
, 9(5), e96766-e96766.
Zangger Haroun, Ronet Catherine, Desponds Chantal, Kuhlmann F Matthew, Robinson John, Hartley Mary-Anne, Prevel Florence, Castiglioni Patrik, Pratlong Francine, Bastien Patrick, Müller Norbert, Parmentier Laurent, Saravia Nancy Gore, Beverley Stephen M, Fasel Nicolas (2013), Detection of Leishmania RNA virus in Leishmania parasites., in PLoS neglected tropical diseases
, 7(1), 2006-2006.
Weinkopff Tiffany, Mariotto Anita, Simon Gregoire, Hauyon-La Torre Yazmin, Auderset Floriane, Schuster Steffen, Zangger Haroun, Fasel Nicolas, Barral Aldina, Tacchini-Cottier Fabienne (2013), Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection., in Infection and immunity
, 81(5), 1575-84.
Hartley M-A, Kohl K, Ronet C, Fasel N (2013), The therapeutic potential of immune cross-talk in leishmaniasis., in Clinical microbiology and infection : the official publication of the European Society of Clinical M
, 19(2), 119-30.
Hartley Mary-Anne, Ronet Catherine, Fasel Nicolas (2012), Backseat drivers: the hidden influence of microbial viruses on disease., in Current opinion in microbiology
, 15(4), 538-45.
Hartley Mary-Anne, Ronet Catherine, Zangger Haroun, Beverley Stephen M, Fasel Nicolas (2012), Leishmania RNA virus: when the host pays the toll., in Frontiers in cellular and infection microbiology
, 2, 99-99.
Ronet Catherine, Beverley Stephen M, Fasel Nicolas (2011), [Mucocutaneous leishmaniasis and an undesired passenger]., in Médecine sciences : M/S
, 27(11), 924-6.
Meslin Benoît, Zalila Habib, Fasel Nicolas, Picot Stephane, Bienvenu Anne-Lise (2011), Are protozoan metacaspases potential parasite killers?, in Parasites & vectors
, 4, 26-26.
Ives Annette, Ronet Catherine, Prevel Florence, Ruzzante Giulia, Fuertes-Marraco Silvia, Schutz Frederic, Zangger Haroun, Revaz-Breton Melanie, Lye Lon-Fye, Hickerson Suzanne M, Beverley Stephen M, Acha-Orbea Hans, Launois Pascal, Fasel Nicolas, Masina Slavica (2011), Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis., in Science (New York, N.Y.)
, 331(6018), 775-8.
Ronet Catherine, Beverley Stephen M, Fasel Nicolas (2011), Muco-cutaneous leishmaniasis in the New World: the ultimate subversion., in Virulence
, 2(6), 547-52.
Meslin B, Beavogui AH, Fasel N, Picot S (2011), Plasmodium falciparum Metacaspase PfMCA-1 Triggers a z-VAD-fmk Inhibitable Protease to Promote Cell Death, in PLOS ONE
, 6(8), 1-11.
Zalila Habib, González Iveth J, El-Fadili Amal Kuendig, Delgado Maria Belen, Desponds Chantal, Schaff Cédric, Fasel Nicolas (2011), Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major., in Molecular microbiology
, 79(1), 222-39.
Fuertes Marraco Silvia A, Scott Clare L, Bouillet Philippe, Ives Annette, Masina Slavica, Vremec David, Jansen Elisa S, O'Reilly Lorraine A, Schneider Pascal, Fasel Nicolas, Shortman Ken, Strasser Andreas, Acha-Orbea Hans (2011), Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo., in PloS one
, 6(6), 20189-20189.
The human protozoan parasites Leishmania (L.) are the causative agents of leishmaniasis, which can lead, depending on the species, to either cutaneous or mucocutaneous lesions, or fatal generalized visceral infection. For example, L. major is the causative agent of cutaneous leishmaniasis (CL), while New World Leishmania (Viannia) subgenus species causes mucocutaneous leishmaniasis (MCL).Currently, the mechanisms involved in MCL development are poorly understood but differ from CL pathology. Clinical MCL involves parasitic dissemination (metastasis) to the nasopharyngeal areas of the face leading to destructive metastatic secondary lesions with hyper-inflammatory immune responses. Approximately, 5-10% of individuals with resolved L. (Viannia) CL primary lesions develop MCL. We recently found that metastasizing, but not non-metastatic parasites have high burden of a dsRNA virus, Leishmania RNA Virus-1 (LRV1) that is sensed by the host Toll-like Receptor 3 (TLR3) thereby inducing a pro-inflammatory cytokine and chemokine response, which is a hallmark of this disease in MCL patients. Paradoxically, the TLR3 mediated-IFN-ß response renders mice more susceptible to infection, with increased footpad swelling and parasite load. Thus, LRV1 in the metastasizing parasites subverts the host immune response to L. (Viannia) species thereby promoting parasite persistence and dissemination.Our proposal is aimed at better defining the connection between the parasite carrying LRV1 and the host immune response. We plan to investigate the mechanism whereby LRV1 confers increased susceptibility to infection with L. (Viannia) parasites rather than an anti-viral resistance and will analyze the critical role of IFN-ß played in the host immune response. To this end, we will (1) compare LRV1 harboring L. guyanensis parasites to LRV1 negative L. guyanensis lines with emphasis on nitric oxide (NO) and superoxide production, (2) investigate how LRV1, and the associated hyper-inflammatory immune response of the host are implicated in the metastatic phenotype and (3) examine whether anti-inflammatory drugs with an anti-Leishmania activity can prevent the development of mucocutaneous leishmaniasis. Our results should help defining the role of LRV1 in MCL pathology and ultimately facilitate the introduction of new clinical strategies to fight MCL.