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Host cellular responses and early innate immunity to Leishmania infection

English title Host cellular responses and early innate immunity to Leishmania infection
Applicant Fasel Nicolas Joseph
Number 164176
Funding scheme Bilateral programmes
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 01.03.2016 - 28.02.2019
Approved amount 250'000.00
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All Disciplines (3)

Discipline
Biochemistry
Experimental Microbiology
Cellular Biology, Cytology

Keywords (8)

Leishmania; Toll-like Receptors; Innate immune response; PKR; ER-Stress Response; Kinases; Autophagy; Anti-Leishmania drugs

Lay Summary (French)

Lead
Douze millions de personnes infectées par le parasite protozoaire Leishmania. Ces parasites transmis par une piqûre d’une mouche hématophage sont phagocytés par le macrophage et survivent et se multiplient dans le phagolysosome correspondant à un environnement hostile. Les manifestations cliniques différent selon les espèces de Leishmania, allant d’une leishmaniose cutanée, aux leishmanioses viscérale et muco-cutanée. Dans ce dernier cas, l’infection va de pair avec une forte inflammation, des ulcérations cutanées plus extensives et un fort potentiel de dissémination en des sites secondaires distants du site initial allant jusqu’à une atteinte des muqueuses naso-pharyngées.
Lay summary

La présence d’un virus à ARN double brin (LRV) dans Leishmania guyanensis joue un rôle déterminant dans la réponse hyper-inflammatoire et participe à la difficulté de traitement observée chez les patients, qui relapsent plus fréquemment et doivent subir des traitements supplémentaires. La réponse innée de l’hôte suite à cette co-infection induit la production d’interféron-beta (IFN-beta). De manière similaire, Leishmania amazonensis induit aussi de l’interféron-béta bien que la présence de LRV n’ait pas été démontrée. L’étude que nous proposons  est centrée autour de L. guyanensis et de L. amazonensis et de la production d’IFN-beta, des kinases de l’hôte activées par l’infection et l’impact sur le métabolisme de la cellule infectée, le rôle de l’autophagie et le flux glycolytique précoce. Nos travaux avec le Brésil devraient nous permettre de définir quel est l’impact de l’infection sur le métabolisme de la cellule pour la mise en place de nouvelles approches thérapeutiques.

Direct link to Lay Summary Last update: 29.12.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β
Hartley Mary-Anne, Eren Remzi O., Rossi Matteo, Prevel Florence, Castiglioni Patrik, Isorce Nathalie, Desponds Chantal, Lye Lon-Fye, Beverley Stephen M., Drexler Stefan K., Fasel Nicolas (2018), Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β, in Microbial Cell, 5(3), 137-149.
Development of a semi-automated image-based high-throughput drug screening system
Eren R.O. Kopelyanskiy D. Moreau D. Chapalay J.B. Chambon M. Turcatti G. Lye L.F. Beverley S. (2018), Development of a semi-automated image-based high-throughput drug screening system, in Frontiers in bioscience, 10, 242-253.
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.
Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis.
Rossi M. Castiglioni P. Hartley M.A. Eren R.O. Prével F. Desponds C. Utzschneider D.T. Zehn D (2017), Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis., in PNAS, 114(19), 4987-4992.
Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor
Kuhlmann F. Matthew, Robinson John I., Bluemling Gregory R., Ronet Catherine, Fasel Nicolas, Beverley Stephen M. (2017), Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor, in Proceedings of the National Academy of Sciences, 114(5), E811-E819.
Macrophage Survival Assay Using High Content Microscopy
Eren RO Fasel N (2017), Macrophage Survival Assay Using High Content Microscopy, in Bio-Protocol, 7(16), 2509.
Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence.
Eren Remzi Onur, Reverte Marta, Rossi Matteo, Hartley Mary-Anne, Castiglioni Patrik, Prevel Florence, Martin Ricardo, Desponds Chantal, Lye Lon-Fye, Drexler Stefan K, Reith Walter, Beverley Stephen M, Ronet Catherine, Fasel Nicolas (2016), Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence., in Cell host & microbe, 20(3), 318-28.
Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism
Calegari-Silva TC Vivarini ÁC Pereira RMS Dias-Teixeira KL Rath CT Pacheco ASS Silva GBL Pint, Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism, in Eur J Immunol.

Collaboration

Group / person Country
Types of collaboration
Prof. Fabio Martinon, Département de Biochimie, UNIL, Epalinges Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
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
Instituto de Biofisica Carlos Chagas Fiho Brazil (South 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
Emergences et Persistances Individual talk Leishmaniose sévère et RNA virus : un clandestin dangereux 04.04.2019 Montpellier, France Fasel Nicolas Joseph;
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 associates 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;
6th World Congress on Leishmaniasis Talk given at a conference Metastatic leishmaniasis 16.05.2017 Toledo, Spain Fasel Nicolas Joseph;
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;
the XXXII Annual Meeting of the Brazilian Society of Protozoology / XLIII Annual Meeting on Basic Research in Chagas Disease Talk given at a conference A novel evasion strategy of host cell defense by Leishmania: induction of the PERK/eIF2alpha/ATF-4 axis 07.11.2016 Caxambu, Minas Gerais, , Brazil Gazos Lopes Ulisses;
45th Annual Meeting of the Brazilian Society for Bioche Annual Meeting of the Brazilian Society for Biochemistry and Molecular Biology (SBBq Talk given at a conference The NFKB1/HDAC1 complex controls the outcome of Leishmania infection in human macrophages 18.06.2016 ), Natal, Rio Grande do Norte, , Brazil Gazos Lopes Ulisses;
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;
Lecture series Talk given at a conference Signaling and control of gene expression in Leishmania-infected macrophages 04.05.2016 Universidade de São Paulo, Ribeirão Preto, Brazil Gazos Lopes Ulisses;


Associated projects

Number Title Start Funding scheme
173180 Impact of viral infections on metastatic leishmaniases 01.04.2017 Project funding (Div. I-III)
153204 Impact of Leishmania dsRNA virus on metastatic leishmaniases 01.04.2014 Project funding (Div. I-III)

Abstract

Patients infected with Leishmania protozoan parasites present either cutaneous lesions (CL) at the site of the sand fly bite or metastatic leishmaniases such as visceral (VL) and Post Kala-Azar dermal (PKDL), disseminated (DCL), diffuse (DL) and mucosal (ML) forms. The poor immunologic control can be due to susceptibilities of the host or parasite virulence factors influencing the host cell innate immune response and the survival of the infected cell. The signalling cascades, induced by the infection, are triggered by various Pattern Recognition Receptors such as the Toll-like Receptors (TLRs), many of them being intricately involved in leishmanial immune response.In South America, New World Leishmania (L.) species such as L. amazonensis and L. guyanensis can subvert the innate immune system of the host to survive and induce metastatic leishmaniasis. In both cases, the exacerbation was caused by the production of type I Interferons (IFNs-I). Thanks to the work of the two applicants, the signalling cascades triggering IFN-I have been linked to Leishmania RNA virus (LRV) present in L. guyanensis and activating the Toll-like Receptor 3 (TLR3) and to the dsRNA dependent Protein Kinase (PKR) in L. amazonensis infections respectively. These two immune evasion strategies leading to exacerbation of the disease could use convergent or different pathways.Results obtained in Switzerland demonstrated that the presence of a viral endosymbiont (LRV) found naturally inside L. guyanensis parasites triggered TLR3, induced IFN-beta secretion, pro-inflammatory chemokines and cytokines, exacerbated the pathology possibly by increasing survival of infected macrophages. Preliminary experimental evidence suggested that, in the infected macrophage, LRV-activated TLR3 induced AKT1, a pro-survival kinase, and thereby down-regulating apoptosis of the infected macrophage. Interestingly, LRV-activated TLR3 induces the microRNA (miR155), which is known to trigger autophagy in macrophages. Results obtained in Brazil with L. amazonensis (which causes CL and also disseminated leishmaniasis) demonstrated that the dsRNA-dependent kinase (PKR) is activated in L. amazonensis infected macrophages leading to the expression of IL-10 and IFN-beta. The PKR/IFN-beta axis plays a pivotal role on the parasite intracellular replication and results obtained in human biopsies from CL and ADCL patients revealed a dramatic increase of PKR and IFN1 expression in the latter group, thus indicating an important role in the severity of the disease. Moreover, our data suggests that ER stress is induced in L. amazonensis infected cells and may control the progression of the infection throughout the expression IFN-beta and the activation of the NF-E2-related factor 2 (Nrf2). The data obtained by Brazilian group shows that Nrf2, a transcription factor that control the expression of anti-oxidative responsive genes, is translocated to nuclei of infected macrophage, binds to the ARE (Antioxidant Responsive Elements) sequences of genes such as SOD1 and seems to relief the oxidative stress due to the infection. Importantly, PKR and AKT1 activation are required for Nrf2 signalling in the context of the infection.How these different kinases ending up with IFN-beta secretion modulate survival of the infected macrophage and are relevant to the clinical complications is not clear. This proposal aims at investigating the relevance of host cell kinases in L. guyanensis and L. amazonensis infections and to define how they program the host cell to the advantage of the parasites and infected macrophage survival. Both groups will investigate specific kinases, kinase signaling pathways and downstream targets in infected macrophages. Emphasis will be put on the pro-survival kinase, AKT1 which blocks apoptosis, induces an early glycolytic flux, regulates the mammalian Target of Rapamycin complex (mTORC1), and consequently autophagy (AIM 1) and on the Endoplasmic Reticulum (ER) stress response (AIM 2) in macrophages infected with LRV+ or LRV- L. guyanensis as well with L. amazonensis. A major obstacle in controlling leishmaniases is the variation in drug responsiveness across different species, thus, finding common ground in druggable pathways such as autophagy and ER stress response, brings much promise. Our results will not only improve our understanding of host-parasite interactions but should, at the end, propose new therapeutics to disrupt the pathogenic evasion strategies. It could have an impact not only on L. guyanensis and L. amazonensis infections but also on other types of Leishmania spp. infections. It will also give essential information on the changes induced on the metabolism of the host cell.
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