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Impact of viral infections on metastatic leishmaniases

English title Impact of viral infections on metastatic leishmaniases
Applicant Fasel Nicolas Joseph
Number 173180
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 01.04.2017 - 31.07.2020
Approved amount 868'269.00
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All Disciplines (3)

Discipline
Biochemistry
Cellular Biology, Cytology
Experimental Microbiology

Keywords (7)

Toll-like Receptors; Inflammation; Leishmania; Metastasis; Macrophages; Leishmania RNA virus; LCMV

Lay Summary (French)

Lead
La présence de virus symbiotiques dans des parasites protozoaires peut exacerber les symptômes observés chez les patients. La présence de ces virus est donc un facteur aggravant dont il faut tenir compte pour définir le traitement adéquat.Les parasites Leishmania causent principalement des lésions cutanées primaires au site de piqûre par une mouche des sables. Ces lésions sont souvent ulcérées. Les traitements actuels ne sont pas pleinement satisfaisants soit par l’apparition de résistance soit par leurs effets secondaires. De plus, lors d’infection par certaines espèces de Leishmania, les patients rechutent facilement et les traitements proposés ne sont pas très efficaces.
Lay summary

Récemment, nous avons démontré que la présence du virus symbiotique, Leishmania RNA virus (LRV) dans des souches de leishmanies détournait le système immunitaire, exacerbait la pathologie, était une des causes de la dissémination de l’infection et que la présence de LRV était probablement une des raisons pour des rechutes plus fréquentes. Ces infections sont caractérisées par une forte réponse inflammatoire et par la présence d’une réponse antivirale due à la présence de LRV. Notre étude va permettre de définir quelle est le mécanisme sous-jacent à la métastatisation de l’infection, quelles sont les cellules qui transportent le parasite du site initial d’infection à des sites secondaires, comment d’autres virus peuvent faire de même lors de co-infections ou d’infections ultérieures. Enfin, nous pourrons définir les mécanismes expliquant comment les parasites peuvent échapper au traitement en modulant la réponse de la cellule hôte expliquant certains cas de résistance.

Direct link to Lay Summary Last update: 03.04.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis
Dias-Teixeira Karina Luiza, Calegari-Silva Teresa C., Medina Jorge M., Vivarini Áislan C., Cavalcanti Átila, Teteo Nataly, Santana Alynne Karen M., Real Fernando, Gomes Ciro M., Pereira Renata Meirelles Santos, Fasel Nicolas, Silva João S., Aktas Bertal H., Lopes Ulisses G. (2017), Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis, in Scientific Reports, 7(1), 17074-17074.
Magnesium uptake by connecting fluid-phase endocytosis to an intracellular inorganic cation filter
Klompmaker Sandra H., Kohl Kid, Fasel Nicolas, Mayer Andreas (2017), Magnesium uptake by connecting fluid-phase endocytosis to an intracellular inorganic cation filter, in Nature Communications, 8(1), 1879-1879.
Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis
Vivarini Áislan de Carvalho, Calegari-Silva Teresa Cristina, Saliba Alessandra Mattos, Boaventura Viviane Sampaio, França-Costa Jaqueline, Khouri Ricardo, Dierckx Tim, Dias-Teixeira Karina Luiza, Fasel Nicolas, Barral Aldina Maria Prado, Borges Valéria Matos, Van Weyenbergh Johan, Lopes Ulisses Gazos (2017), Systems Approach Reveals Nuclear Factor Erythroid 2-Related Factor 2/Protein Kinase R Crosstalk in Human Cutaneous Leishmaniasis, in Frontiers in Immunology, 8, 1127.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ICGEB, Molecular Biology of Leishmania Talk given at a conference Host parasite interactions and viral co-infections 22.10.2018 Trieste, Italy Fasel Nicolas Joseph;
EMBO workshop "Molecular advances and parasite strategies in host infection" Talk given at a conference The impact of viral backseat drivers on leishmaniasis 30.09.2018 Les Embiez, France Fasel Nicolas Joseph;
Swiss Society For Microbiology Talk given at a conference Leishmania parasites and assocites 28.08.2018 Lausanne, Switzerland Fasel Nicolas Joseph;
Seminar series, Department of Experimental Virology , University of Basel Talk given at a conference Metastatic Parasitosis: the viral beast within! 21.09.2017 Basel, Switzerland Fasel Nicolas Joseph;
World Leishmania VI meeting Talk given at a conference Metastatic leishmaniasis 16.05.2017 Toledo, Spain Fasel Nicolas Joseph;
Swiss Biotech Day Talk given at a conference Impact and complexity of co-infections on therapeutic approaches 04.05.2017 Congress Center Basel, Basel, Switzerland Fasel Nicolas Joseph;


Associated projects

Number Title Start Funding scheme
153204 Impact of Leishmania dsRNA virus on metastatic leishmaniases 01.04.2014 Project funding (Div. I-III)
164176 Host cellular responses and early innate immunity to Leishmania infection 01.03.2016 Bilateral programmes

Abstract

The endosymbiosis of viruses in microbes is a well-described and prevalent environmental partnership, where viruses offer their microbial host incentives of fitness in exchange for the use of their metabolic machinery and of virulence, when the microbial host is a pathogen. In the last few years, our group has described this last notion as a fundamental factor in exacerbated and metastatic lesions of mucocutaneous leishmaniasis (MCL), a pathological form often difficult to treat and subject to relapses after a first-line drug treatment. We reported that the dsRNA of the Leishmania RNA virus (LRV), a viral endosymbiont residing inside the Leishmania human protozoan parasites, is recognized by the host cell Toll-like Receptor 3 (TLR-3) causing a destructive inflammatory response, exacerbating the disease and causing metastasis of the infection. In this context, we reported the detrimental role of LRV-dependent type-1 IFNs as promoting inflammatory cytokines and chemokines; the impact of LRV on the enhanced survival of infected macrophages via expression of miR-155 and phosphorylation of the Akt pro-survival kinase; on the relevance of IL-17 in the dissemination of the infection using a mouse metastatic model and on favoring relapses in patients after a first-line drug treatment. These pathological outcomes are driven by subverting the innate immune response to the advantage of the parasite and its viral passenger. Although we described essential mediators of this TLR-3-driven subversion of the host response, there is still no information on how primary and secondary lesions are formed, on the types of infected cells (the cargo cells) and the mechanism(s) implicated in the metastasis of the infection. In addition, other co-infecting viruses could play the same role as the endosymbiotic LRV. The aims of the experiments included in this research proposal are to determine: 1) which are the cell types and the mechanisms underlying the LRV-dependent dissemination of the infection to secondary sites and lesion formation; 2) the impact of other viruses on exacerbation, relapses and metastasis of Leishmania infection and the underlying mechanisms; 3) the molecular mechanisms relevant to relapses of the infection in patients previously exposed to a first-line drug treatment. To achieve these goals, we will use two mouse metastatic leishmaniasis models we developed in order to characterize the exacerbation of the primary lesion, to identify which cargo cells are implicated in the metastatic process and to determine the mechanisms of dissemination and secondary lesion formation firstly in LRV-dependent pathology and secondly in viral co-infection. Considering that LRV-dependent TLR-3 activation has an impact on relapses in drug-treated patients, we will investigate the signaling pathways important in this form of resistance and determine how LRV subverts the anti-oxidant response of the mammalian to the advantage of its parasite host.In conclusion, our research on LRV and co-infecting viruses will provide seminal information on the exacerbation and dissemination in MCL and on how parasites and other co-infecting viruses can subvert the innate immune response to escape anti-Leishmania drugs. These results will bring new concepts relevant not only to the Leishmania field but also to several other pathologies, including new emerging infectious diseases and the relevance of the innate immune response on resistance to drugs.
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