Project

Back to overview

Impact of Leishmania dsRNA virus on metastatic leishmaniases

English title Impact of Leishmania dsRNA virus on metastatic leishmaniases
Applicant Fasel Nicolas Joseph
Number 153204
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 01.04.2014 - 31.03.2017
Approved amount 600'000.00
Show all

All Disciplines (3)

Discipline
Biochemistry
Cellular Biology, Cytology
Experimental Microbiology

Keywords (6)

metastatic leishmaniasis; Leishmania RNA virus; immune response; Leishmania; oxidative stress; antimony response

Lay Summary (French)

Lead
Les leishmanioses sont des infections dues aux leishmanies, des parasites transmis par une piqûre d’une mouche hématophage. On compte environ 12 millions de personnes infectées dans le monde et ce nombre est en augmentation. Il existe plusieurs espèces infectieuses de leishmanies et, selon l’espèce, les manifestations cliniques peuvent être très diverses allant d’une leishmaniose cutanée (LC), aux leishmanioses viscérale et muco-cutanée (LMC). Dans ce dernier cas, les ulcérations cutanées sont plus extensives et l’infection a un fort potentiel de dissémination en des sites distants du site d’infection voire d’atteinte des muqueuses des régions naso-pharyngées.
Lay summary

Contenu et objectifs du travail
Nous avons récemment démontré qu’un virus, présent dans certaines espèces de leishmanies, joue un rôle déterminant pour le développement d’une réponse hyper-inflammatoire et aggravante  chez l’hôte. Cette réponse dépend de la production d’interféron-bêta. Paradoxalement, la présence du virus participe à la production de molécules toxiques pour le parasite. Le parasite et son virus doivent donc pouvoir détoxifier ces molécules afin de survivre dans le macrophage, la cellule hôte du parasite. Notre étude va permettre de préciser quelles sont les voies métaboliques induites par le parasite et son virus pour survivre dans cet environnement toxique, c.à.d. quels sont les mécanismes de détoxification utilisés et, dans ce contexte, comment des produits comme l’antimoine, utilisé couramment pour traiter les leishmanioses, active ces mêmes voies de détoxification, diminuant son efficacité chez le patient. Ces travaux doivent permettre de comprendre certains cas de résistance aux anti-leishmanies utilisés et la mise en place de nouvelles approches thérapeutiques.

Direct link to Lay Summary Last update: 07.04.2014

Lay Summary (English)

Lead
Leishmaniases are human infections caused by Leishmania protozoan parasites, endemic in 98 countries and affecting 12 million patients. Different pathologies are induced by Leishmania parasites depending on the infectious species, ranging from cutaneous lesions developing at the site of a female sand fly bite to visceralized or metastatic leishmaniases. In metastatic leishmaniases, parasites disseminate to secondary cutaneous and/or mucosal sites. Parameters implicated in this dissemination are poorly described. Inflammation and relapses after the first line of treatment (antimony) are the main hallmarks of metastatic leishmaniases. This project is aimed at answering this problem.
Lay summary

Content and objectives
We have demonstrated that a virus (LRV) inside parasites impacts on the response of the host, aggravating Leishmania pathologies. This exacerbation is a consequence of a very early induction of interferon-β, responsible for the production of inflammatory mediators. Paradoxically, LRV up-regulates pathways responsible for the release of molecules toxic for the parasite.
In the context of this complex situation, we will focus on how LRV impacts on parasite survival by studying pathways in the parasite host resident cell, the macrophage, and confirm that LRV inside the parasite participates in the detoxification of toxic compounds by inducing specific pathways and investigate the impact of antimony on these detoxification machineries. Our results should not only facilitate the introduction of new clinical strategies to fight metastatic leishmaniases, but also improve our understanding of the cross-talk between the immune response and the host metabolism in the context of this host–pathogen interaction and in other co-infections.

Direct link to Lay Summary Last update: 07.04.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid
Castiglioni Patrik, Hartley Mary-Anne, Rossi Matteo, Prevel Florence, Desponds Chantal, Utzschneider Daniel T., Eren Remzi-Onur, Zangger Haroun, Brunner Livia, Collin Nicolas, Zehn Dietmar, Kuhlmann F. Matthew, Beverley Stephen M., Fasel Nicolas, Ronet Catherine (2017), Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid, in PLOS Neglected Tropical Diseases, 11(1), e0005240-e0005240.
Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis
Rossi Matteo, Castiglioni Patrik, Hartley Mary-Anne, Eren Remzi Onur, Prével Florence, Desponds Chantal, Utzschneider Daniel T., Zehn Dietmar, Cusi Maria G., Kuhlmann F. Matthew, Beverley Stephen M., Ronet Catherine, Fasel Nicolas (2017), Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis, in Proceedings of the National Academy of Sciences, 201621447-201621447.
Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A.
Fasel Nicolas (2016), Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A., in Plos Pathogens , pp. e10058.
Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence.
Eren R.O (2016), Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence., in Cell Host and Microbe , 318.
The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis
Hartley M. A., Drexler S., Ronet C., Beverley S. M., Fasel N. (2014), The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis, in Trends in Parasitology, 30(8), 412-422.

Collaboration

Group / person Country
Types of collaboration
Prof. Stephen M. Beverley, Dept of Molecular Microbiology, Washington University in St. Louis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Biotech Day, 2017 Talk given at a conference Impact and Complexity of Co-infections on Therapeutic Approaches” 04.05.2017 Basel, Switzerland Fasel Nicolas Joseph;
Medical Immunology Campus: Immunological Seminar Series Talk given at a conference "Metastatic leishmaniasis" 13.12.2016 Erlangen, Germany Fasel Nicolas Joseph;
Trypanosomatid Parasites: from the field to the lab Talk given at a conference Metastatic leishmaniasis: the viral beast within 26.05.2016 Paris, France Fasel Nicolas Joseph;
Swiss Tropical and Public Helath Institute, Basel Talk given at a conference Metastatic leishmaniasis: the viral beast within 30.03.2016 Basel, Switzerland Fasel Nicolas Joseph;
Institut de Microbiologie Fondamentale Talk given at a conference Metastatic leishmaniasis: the viral beast within 05.02.2016 Lausanne, Switzerland Fasel Nicolas Joseph;
Les Lundis de l'IPSIT: Institut Paris Saclay Innovation Thérapeutique Talk given at a conference “Leishmaniasis : un ménage à trois “ 14.12.2015 Paris, France Fasel Nicolas Joseph;
COST action meeting CM1307, Belgrade Talk given at a conference High content microscope based high - throughput drug screening against double - stranded endoymbiont Leishmania RNA virus containing Leishmania guyanensis using primary murine macrophages 26.10.2015 Belgrade, Serbien Fasel Nicolas Joseph;
4th Conference on Protein Kinase of Parasitic Protozoa Talk given at a conference 4th Conference on Protein Kinase of Parasitic Protozoa 22.03.2015 Haifa, Israel 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;


Associated projects

Number Title Start Funding scheme
173180 Impact of viral infections on metastatic leishmaniases 01.04.2017 Project funding (Div. I-III)
135616 Impact of Leishmania dsRNA virus on mucocutaneous leishmaniasis 01.04.2011 Project funding (Div. I-III)
164176 Host cellular responses and early innate immunity to Leishmania infection 01.03.2016 Bilateral programmes
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'

Abstract

Protozoan Leishmania parasites have been plaguing humans for centuries. They reside within host macrophages in a phagolysosome-like organelle, impacting on host metabolism and immune response. Different types of pathologies are induced by Leishmania parasites depending on the infectious species, ranging from cutaneous lesions developing at the site of a female sand fly bite to visceralized or metastatic leishmaniases. In metastatic leishmaniases, parasites disseminate to secondary cutaneous and/or mucosal sites. These clinical presentations are mainly found in Leishmania (L.) braziliensis, L. panamensis and L. guyanensis infected patients. Parameters implicated in this dissemination are poorly described. Inflammation and relapses after the first line of treatment (antimony) are the main hallmarks of metastatic leishmaniases.We have demonstrated that the presence of an endosymbiotic dsRNA virus (LRV) inside L. guyanensis parasites impacts on the immune and cellular response of the host, aggravating Leishmania pathologies. LRV dsRNA binds to the endosomal Toll-like receptor 3 (TLR3) and exacerbates the disease in our animal models, causing larger lesions and increasing parasite survival and consequently parasite burden. This exacerbation is a consequence of a very early induction of interferon-ß, which is responsible for the production of inflammatory cytokines and chemokines such as interleukin-6 and tumor necrosis factor-a, markers known to be relevant in chronic inflammation in mucosal leishmaniasis patients. Paradoxically, while LRV helps in maintenance and survival of parasites, it also up-regulates inducible nitric oxide synthase, responsible for the production and release of higher levels of nitric oxide and peroxinitrite, which participates in the killing of most Leishmania parasites. The mechanisms behind the LRV-dependent parasite survival, the oxidative stress environment and the TLR3 activation and their impact on relapses after antimony treatment are not known. Our recent data strongly suggest that there is a link between TLR3, microRNA-155 and heme-oxygenase-1 as well as between parasite entry, reactive oxygen species and the detoxification machinery. The timing of these responses is critical and the events taking part in the first hours of infection are essential for an increased LRV-dependent parasite survival and to determine the outcome of disease. Thus, in the context of this complex situation, an intracellular parasite and its endosymbiotic virus, and based on our previous data, we will focus on how LRV impacts on parasite survival by studying two macrophage pathways involved in detoxification: the NF-E2-related factor 2/microRNA-155/heme oxygenase-1 pathway (AIM 1), the peroxiredoxins/sulfiredoxin pathway (AIM 2) and also by investigating the impact of antimony in the context of this nested co-infection and detoxification machineries (AIM 3). Our results should not only facilitate the introduction of new clinical strategies to fight metastatic leishmaniases, but also improve our understanding of the cross-talk between the immune response and the host metabolism in the context of this host-pathogen interaction and in other co-infections.
-