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Tuning of immune homeostasis and immune response by persistent viral infections

English title Tuning of immune homeostasis and immune response by persistent viral infections
Applicant Lanzavecchia Antonio
Number 147662
Funding scheme Sinergia
Research institution Istituto di Ricerca in Biomedicina (IRB)
Institution of higher education Università della Svizzera italiana - USI
Main discipline Immunology, Immunopathology
Start/End 01.08.2013 - 31.07.2016
Approved amount 1'998'271.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Clinical Immunology and Immunopathology

Keywords (6)

cytomegalovirus; innate immunity; adaptive immunity; chronic viral infection; immune ageing ; HIV

Lay Summary (Italian)

Lead
La risposta immunitaria richiede l’azione coordinata di diverse cellule che sono costantemente esposte a microrganismi commensali (microbioma) e a virus che stabiliscono infezioni croniche (viroma). Partendo da recenti studi che hanno dimostrato che il microbioma è in grado di modulare la risposta immunitaria, questo progetto si propone di valutare come il viroma influenza la composizione, le proprietà e la funzione delle cellule immunitarie, nell’uomo e in modelli animali.
Lay summary
Lo scopo di questo progetto è di capire se e come le infezioni virali croniche incidano sulla risposta immunitaria ai vaccini, sulla suscettibilità alle infezioni, sulla predisposizione all’autoimmunità e sull’invecchiamento del sistema immunitario. Tre centri clinici e di ricerca situati a Bellinzona, Losanna e Zurigo con diverse compentenze e risorse complementari collaboreranno per raggiungere questo ambizioso obiettivo. Il sistema immunitario di pazienti con infezioni virali croniche verrà studiato utilizzando tecnologie analitiche cellulari e molecolari di ultima generazione, quali la citometria a flusso abbinata alla spettrometria di massa, il profilo di espressione genica su singole cellule e sequenziamento del repertorio. Studi in modelli murini di infezione cronica completeranno gli studi umani. Combinando i dati ottenuti nei tre centri questo progetto Sinergia darà luogo alla visione più completa dell'impatto delle infezioni virali croniche sull’omeostasi e la funzionalità del sistema immunitario.
Direct link to Lay Summary Last update: 16.09.2013

Lay Summary (English)

Lead
The immune response relies on the coordinated action of different cells of the immune system, which are constantly confronted with commensal microorganisms (microbiome) and with persistent viral infections (virome). In contrast to the microbiome, which has been shown to modulate the immune response, the virome received much less attention. This project therefore aims at assessing how the virome impacts the composition, properties and function of immune cells, in both humans and animal models.
Lay summary
In this project, we aim to understand to what extent chronic viral infections impact on the response to vaccines, on the susceptibility to infection, on the predisposition to autoimmunity and on the acceleration of immunological ageing. Three research and clinical centers located in Bellinzona, Lausanne, and Zurich will cooperate to reach this ambitious goal. They will take advantage of complementary expertise and resources to study well defined cohorts of patients with chronic viral infections using state-of-the-art analytical technologies such as multiparameter and mass-tag barcoding flow cytometry, single cell gene expression profiling, high throughput cellular screening methods and with next generation repertoire sequencing. Studies in mouse models of chronic infection will complement and synergize with the human studies. By combining the data obtained in the three centers this Sinergia project will give rise to the most comprehensive view of the impact of chronic viral infections on the homeostasis and the functionality of the immune system.
Direct link to Lay Summary Last update: 16.09.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Emerging single-cell technologies in immunology.
Herderschee Jacobus, Fenwick Craig, Pantaleo Giuseppe, Roger Thierry, Calandra Thierry (2015), Emerging single-cell technologies in immunology., in Journal of leukocyte biology, 98(1), 23-32.
Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus.
Corti Davide, Zhao Jincun, Pedotti Mattia, Simonelli Luca, Agnihothram Sudhakar, Fett Craig, Fernandez-Rodriguez Blanca, Foglierini Mathilde, Agatic Gloria, Vanzetta Fabrizia, Gopal Robin, Langrish Christopher J, Barrett Nicholas A, Sallusto Federica, Baric Ralph S, Varani Luca, Zambon Maria, Perlman Stanley, Lanzavecchia Antonio (2015), Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus., in Proceedings of the National Academy of Sciences of the United States of America, 112(33), 10473-8.
T cell immunity. Functional heterogeneity of human memory CD4⁺ T cell clones primed by pathogens or vaccines.
Becattini Simone, Latorre Daniela, Mele Federico, Foglierini Mathilde, De Gregorio Corinne, Cassotta Antonino, Fernandez Blanca, Kelderman Sander, Schumacher Ton N, Corti Davide, Lanzavecchia Antonio, Sallusto Federica (2015), T cell immunity. Functional heterogeneity of human memory CD4⁺ T cell clones primed by pathogens or vaccines., in Science (New York, N.Y.), 347(6220), 400-6.
Proteome-wide analysis of HIV-specific naive and memory CD4(+) T cells in unexposed blood donors.
Campion Suzanne L, Brodie Tess M, Fischer William, Korber Bette T, Rossetti Astrea, Goonetilleke Nilu, McMichael Andrew J, Sallusto Federica (2014), Proteome-wide analysis of HIV-specific naive and memory CD4(+) T cells in unexposed blood donors., in The Journal of experimental medicine, 211(7), 1273-80.

Collaboration

Group / person Country
Types of collaboration
Prof A. McMichael, University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr M. Cavassini / CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Raphael Gottardo, Fred Hutchinson Research Center, Seattle United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Lanzavecchia's group / Institute for Research in Biomedicine Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof A. Rauch / UniBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Bernd Bodenmiller, Institute of Molecular Life Sciences, University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof De Moradpour / CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Calandra's group / CHUV Infectious Diseases Service Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jean-Marc Corpataux, Division of Vascular Surgery, CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christian Simon, Service of ENT, CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. A. Calmy / UniGE Switzerland (Europe)
- 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
Meeting of the Swiss Immunology PhD students, Wolfsberg Talk given at a conference The immune function in chronic viral infections 26.03.2015 Wolfsberg, Switzerland Barnstorf Isabel;
Meeting of the Swiss Immunology PhD students, Wolfsberg Poster Emerging single-cell technologies in immunology 26.03.2015 Wolfsberg, Switzerland Herderschee Jacobus;
The 9th WIRM 2015 Talk given at a conference Immune function in chronic viral infections 20.03.2015 Davos, Switzerland Barnstorf Isabel;
Fourth international retreat: viral infection, immunity and autoimmunity Talk given at a conference Immune function in chronic viral infections 01.01.2015 Koblenz, Germany Barnstorf Isabel;
XXV I Meeting of the Swiss Immunology PhD students Poster Tuning of innate immune homeostasis by persistent viral infections 14.04.2014 8272 Ermatingen, Switzerland Herderschee Jacobus;
XXVI Meeting of the Swiss Immunology PhD students Wolfsberg Poster Impact of persistent viral infections on immune responsiveness in mice 14.04.2014 Schloss Wolfsberg, Switzerland Barnstorf Isabel;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Sinergia 147662 IRB web site International 2013

Awards

Title Year
The 2018 Louis-Jeantet Prize for Medicine conferred to Prof. Antonio Lanzavecchia 2018
2017 Robert Koch Prize to Prof. Antonio Lanzavecchia 2017
Antonio Lanzavecchia receives the 2017 Sanofi-Institut Pasteur Award 2017
Jacobus Herderschee was selected by the competitive PhD Program in Cancer and Immunology from the University of Lausanne 2014

Associated projects

Number Title Start Funding scheme
157699 Acquisition of a 600MHz solution NMR spectrometer 01.10.2015 R'EQUIP

Abstract

Immune responsiveness of a host towards microbial challenges or vaccines is given by the various constituents of the immune system, which are subjected to different types of modulation. Such modulation is the result of the previous infection/vaccine history of an individual, the constant confrontation with commensal microorganisms at mucosal surfaces (the "microbiome") and the constant exposure to persistent viral infections (the "virome"). Persistent viral infections are widespread in the human population with estimated 8-12 persistent viral infections per individual. Yet, in contrast to the "microbiome", which is increasingly found to modulate immune responses, there is currently very limited knowledge on how persistent viral infections impinge on immune homeostasis and immune responsiveness. The tackle of such complex and medically relevant question is at the center of the present Sinergia application. In this application we propose to comprehensively assess the impact of selected wide-spread persistent viral infections on the overall composition, phenotype and function of various innate and adaptive immune cells, in both humans and mice, with the aim of filling knowledge gaps in our understanding of vaccine efficacy, susceptibility to infection by heterologous pathogens, predisposition to autoimmunity and immunological ageing. Three leading research and clinical centers located in geographically distinct areas (Lausanne, Bellinzona, and Zurich) will synergistically cooperate to reach this ambitious goal. The CHUV teams in Lausanne (G. Pantaleo and T. Calandra) will provide well defined cohorts of patients and will address whether chronic viral infections (using EBV, CMV, HCV and HIV as model viruses) impact on number, diversity, functions, and polarization potential of innate cells (monocytes, conventional and plasmacytoid dendritic cells, and NK cells) and adaptive cells (CD4 and CD8 T lymphocytes) in peripheral blood and tissues. The power of these analyses will be the use of state-of-the-art single cell analytical technologies such as multiparameter flow cytometry, gene expression by Fluidigm and mass-tag barcoding cytometry (CyTOF®). The IRB team in Bellinzona (A. Lanzavecchia) will address how far persistent viral infections alter T and B cell responsiveness towards third party antigens, either in form of vaccines, heterologous infections, or self-antigens. Using high throughput cellular screening methods (T cell libraries, polyclonal B cell activation, B cell immortalization, plasma cell display), complemented with next generation sequencing, these studies will provide a thoroughly analysis of the immune repertoires in different chronic infections and age groups. The ETH team in Zurich (A. Oxenius) will perform studies in mouse models that will complement and synergize with the human studies. Longitudinal and timed analyses will be performed in blood and tissues to directly assign specific immune alterations to a given persistent infection and comparing genetically identical infected and non-infected mice. These studies should provide mechanistic insights into how persistent infections evoke changes in immune responsiveness and immune homeostasis. By combining the data obtained in the three centers this Sinergia project will give rise to the most comprehensive view of the impact of chronic viral infections on the homeostasis and the functionality of the immune system. Thus, the present application contributes to meeting the goals and objectives of the SNF Sinergia programme because it tackles “research fields which necessitate a synergetic research approach in order to address complex and innovative scientific issues”.
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