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Impact of Leishmania dsRNA virus on mucocutaneous leishmaniasis

English title Impact of Leishmania dsRNA virus on mucocutaneous leishmaniasis
Applicant Fasel Nicolas Joseph
Number 135616
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.04.2011 - 31.03.2014
Approved amount 331'000.00
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All Disciplines (3)

Discipline
Biochemistry
Cellular Biology, Cytology
Experimental Microbiology

Keywords (5)

Leishmania; mucocutaneous leishmaniasis; Leishmania RNA virus; immune response; anti-leishmania drugs

Lay Summary (English)

Lead
Lay summary

In Latin America leishmaniasis caused by the Leishmania Viannia (L.Viannia) subgenus is endemic causing cutaneous (CL) and mucocutaneous (MCL) leishmaniasis. Clinical MCL involves parasitic dissemination to the nasopharyngeal areas of the face leading to destructive metastatic secondary lesions and hyper-inflammatory immune responses. Approximately, 5-10% of individuals asymptomatic or with resolved CL lesions can develop MCL, which is associated with persistent immune responses showing pro-inflammatory mediators. In addition to parasite derived virulence factors, host genetics and immune status appear to influence MCL development.

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. Our results should help defining the role of LRV1 in MCL pathology and ultimately facilitate the introduction of new clinical strategies to fight MCL.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Leishmania-RNA virus presence in L.guyanensis parasites increases the risk of first-line treatment failure and symptomatic relapse
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, 105-111.
Implication of different domains of the Leishmania major metacaspase in cell death and autophagy
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.
Cross-presenting dendritic cells are required for control of Leishmania major infection.
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, 1.
Leishmania aethiopica Field Isolates Bearing an Endosymbiontic dsRNA Virus Induce Pro-inflammatory Cytokine Response
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.
MyD88 and TLR9 Dependent Immune Responses Mediate Resistance to Leishmania guyanensis Infections, Irrespective of Leishmania RNA Virus Burden
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.
Detection of Leishmania RNA virus in Leishmania parasites.
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.
Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection.
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.
The therapeutic potential of immune cross-talk in leishmaniasis.
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.
Backseat drivers: the hidden influence of microbial viruses on disease.
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.
Leishmania RNA virus: when the host pays the toll.
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.
[Mucocutaneous leishmaniasis and an undesired passenger].
Ronet Catherine, Beverley Stephen M, Fasel Nicolas (2011), [Mucocutaneous leishmaniasis and an undesired passenger]., in Médecine sciences : M/S, 27(11), 924-6.
Are protozoan metacaspases potential parasite killers?
Meslin Benoît, Zalila Habib, Fasel Nicolas, Picot Stephane, Bienvenu Anne-Lise (2011), Are protozoan metacaspases potential parasite killers?, in Parasites & vectors, 4, 26-26.
Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis.
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.
Muco-cutaneous leishmaniasis in the New World: the ultimate subversion.
Ronet Catherine, Beverley Stephen M, Fasel Nicolas (2011), Muco-cutaneous leishmaniasis in the New World: the ultimate subversion., in Virulence, 2(6), 547-52.
Plasmodium falciparum Metacaspase PfMCA-1 Triggers a z-VAD-fmk Inhibitable Protease to Promote Cell Death
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.
Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major.
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.
Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
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.

Collaboration

Group / person Country
Types of collaboration
CNRS Institut de Chimie des Substances Naturelles France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Les "Lundis de l'IPSIT" - Leishmania, virus and chemotherapy: which gets the last word ? Talk given at a conference Leishmaniasis: un ménage à trois 14.12.2015 Paris, France Fasel Nicolas Joseph;
4th Conference on Protein Kinases of Parasitic Protozoa: Targeting Signaling Pathways in Parasites Talk given at a conference Leishmania RNA virus 1 induces parasite persistence by promoting host survival through an anti-viral immune response 23.03.2015 Haifa, Israel Fasel Nicolas Joseph;
ICGEB course on "Molecular Biology of Leishmania" Talk given at a conference Virulence factors involved in infection 22.10.2014 Trieste, Italy Fasel Nicolas Joseph;
Swiss Virology Meeting Talk given at a conference Metastatic leishmaniasis: the viral beast within ! 09.09.2014 Thun, Switzerland Fasel Nicolas Joseph;
Weiterbildung FMH Tropen- und Reisemedizin - Schweizerische Fachgesellschaft für Tropen- und Reisemedizin FMH Talk given at a conference L'immunologie de la leishmaniose 08.05.2014 Berne, Switzerland Fasel Nicolas Joseph;
NIH/NIAID Twinbrook Seminar Series Individual talk Leishmania RNA virus - a backseat driver in metastatic leishmaniasis 25.03.2014 Rockville, MD, United States of America Fasel Nicolas Joseph;
Seminar Individual talk Metastatic leishmaniasis and a virus in the backseat 24.03.2014 Philadelphia, PA, United States of America Fasel Nicolas Joseph;
5th European Congress of Virology Talk given at a conference Metastatic leishmaniasis and a virus in the backseat 11.09.2013 Lyon, France Fasel Nicolas Joseph;
88th Annual Meeting of the American Society of Parasitologists and 13th Annuel Québec Molecular Parasitology Meeting Talk given at a conference Leishmania RNA virus: a backseat driver to metastatic leishmaniasis 26.06.2013 Québec City, Canada Fasel Nicolas Joseph;
5th World Congress on Leishmaniasis - Worldleish 5 Talk given at a conference Role of interferon-beta in Leishmania RNA Virus-positive Leishmania guyanensis infection 13.05.2013 Porto de Galinhas, PE, Brazil Fasel Nicolas Joseph;
ITM 54th International Colloquium: Pathogens' Survival Strategies Talk given at a conference A tale of a virus and of a parasite 03.12.2012 Antwerp, Belgium Fasel Nicolas Joseph;
ICGEB course on "Molecular Biology of Leishmania" Talk given at a conference Virulence factors involved in infection 24.10.2012 Trieste, Italy Fasel Nicolas Joseph;
Gordon Research Conference on "Biology of Host-Parasite Interactions" Talk given at a conference Metastatic leishmaniasis 10.06.2012 Newport, United States of America Fasel Nicolas Joseph;
European Academy of Microbiology (EAM): Co-infections 2012 Talk given at a conference A tale of a virus and of a parasite 07.06.2012 Halle, Germany Fasel Nicolas Joseph;
Lecture to graduate students Talk given at a conference A tale of a virus and a parasite 04.05.2012 Porto, Portugal Fasel Nicolas Joseph;
XIVèmes Journées Francophones de Virologie Talk given at a conference La leishmaniose mucocutanée: un coupable dans le coupable 29.03.2012 Paris, France Fasel Nicolas Joseph;
22nd Challenge in Virology and SAFE-ID Talk given at a conference A tale on a virus and a parasite 12.01.2012 Saanen Gstaad, Switzerland Fasel Nicolas Joseph;
Indo-Swiss Symposium on Parasitic Diseases / Infectious Diseases Talk given at a conference Muco-cutaneous leishmaniasis in the New World: the ultimate subversion 03.11.2011 New Delhi, India Fasel Nicolas Joseph;
Trypanosomatids 2011: du terrain au laboratoire Talk given at a conference Virulence dans la leishmaniose mucocutanée 27.05.2011 Paris, France Fasel Nicolas Joseph;
Second Forum of the Graduate Schools Infection & Immunity and Biology & Medicine Talk given at a conference Virulent leishmaniasis in South America 19.05.2011 Genève, Switzerland Fasel Nicolas Joseph;
Seminar Individual talk Virulent leishmaniasis in South America 04.05.2011 Basel, Switzerland Fasel Nicolas Joseph;
Kinetoplastid Molecular and Biology Cell Meeting Talk given at a conference Leishmania RNA Virus Controls the Severity of Mucocutaneous Leishmaniasis 08.04.2011 Woods Hole, MA, United States of America Fasel Nicolas Joseph;


Self-organised

Title Date Place
32th Annual Swiss Trypanosomatid Meeting 21.01.2015 Leysin, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Virus sans frontières - 7e édition des Journées de microbiologie Western Switzerland 2014
Talks/events/exhibitions Asociacion Colombiana de Investigadores en Suiza (ACIS), Symposium 2012 International 2012
Media relations: print media, online media Des virus alliés des parasites Horizons FNS German-speaking Switzerland Western Switzerland 2012
Media relations: radio, television Qu'est-ce qu'un parasite protozoaire ? RTS Western Switzerland 2012
New media (web, blogs, podcasts, news feeds etc.) Leishmania RNA virus several websites Western Switzerland International German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
131421 Role of human infection in domestic transmission of dermal leishmaniasis and drug resistance 01.09.2010 Resource not found: 'bd31932a-e257-46d9-9dba-079f6f2c77c6'
145002 Microscale thermophoresis for the Faculty of Bology and Medicine in Lausanne 01.12.2012 R'EQUIP
137340 Leishmania genomics 01.10.2011 International Exploratory Workshops
150799 Advanced analysis of the function of single cells using flow imaging. 01.12.2013 R'EQUIP
153204 Impact of Leishmania dsRNA virus on metastatic leishmaniases 01.04.2014 Project funding (Div. I-III)

Abstract

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.
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