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