Project

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Virus-host balance and pathogenesis in persistent infection

English title Virus-host balance and pathogenesis in persistent infection
Applicant Pinschewer Daniel
Number 114913
Funding scheme SNSF Professorships
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.09.2007 - 31.08.2011
Approved amount 1'575'886.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Microbiology

Keywords (20)

Persistent viral infections; immunopathogenesis; antiviral immuniy; autoimmunity; lymphocytic choriomeningitis virus; T cell escape; antiviral immunity; negative strand RNA virus reverse genetics; immunoprivilege; central nervous system; Persistent viral infections; autoimmunity; T cell escape; antiviral immunity; central nervous system; immunoprivilege; lymphocytic choriomeningitis virus; negative strand RNA virus reverse genetics; antiviral immuniy; immunopathogenesis

Lay Summary (English)

Lead
Lay summary

Project goals:

This projects aims at investigating basic mechanisms how persistent viral infections cause disease, and how the body can successfully eliminate persisting viruses. A better understanding of these processes may help in the future design of vaccines and therapies aimed at combating persistent viral diseases.

Context and significance of the project:

In persistent viral infection, interactions between the virus and the infected body (host) are multifaceted, and different levels of balance can establish between the host and its intruder. Accordingly, persisting viruses can cause a broad range of diseases. Examples are:

a) A growing body of evidence suggests that viruses play a pivotal role in so-called "autoimmune diseases", amongst them multiple sclerosis (MS) that attacks the brain and spinal cord. MS affects up to 0.2% of the human population in high-risk areas and can cause disability in the young. The therapeutic options in MS remain, however, unsatisfactory.

b) Over forty million people worldwide are infected with human immunodeficiency virus (HIV), the causative agent of the AIDS syndrome. Similarly, an estimated number of 170 million people are carriers of hepatitis C virus (HCV) that can cause liver cancer and end-stage liver disease. Yet, protective vaccines against HIV or HCV remain unavailable.

Taken together, persistent viral infections have a tremendous impact on global health. Therefore a better general understanding of persistent viral infection is urgently needed, including better knowledge about successful strategies for defense but also about mechanisms of disease.

Scientific approach and methodology:

This project applies newly developed gene technology (reverse genetics) to one of the best-characterized animal models for persistent viral infection (lymphocytic choriomeningitis virus). The combination thereof with genetically engineered mice, high-end microscope imaging technology and the so-called "gene array" approach (measuring individually but simultaneously the level of activity for all genes) may help shedding light on the complex interactions between virus and host in persistent infection.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Impact of sphingosine 1-phosphate modulation on immune outcomes.
Pinschewer Daniel D, Brinkmann Volker, Merkler Doron (2011), Impact of sphingosine 1-phosphate modulation on immune outcomes., in Neurology, 76(8 Suppl 3), -9.
Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression.
Bergthaler Andreas, Flatz Lukas, Hegazy Ahmed N, Johnson Susan, Horvath Edit, Löhning Max, Pinschewer Daniel D (2010), Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression., in Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21641-6.
Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.
Pinschewer Daniel D, Flatz Lukas, Steinborn Ralf, Horvath Edit, Fernandez Marylise, Lutz Hans, Suter Mark, Bergthaler Andreas (2010), Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes., in International immunology, 22(9), 749-56.
The role of CD80/CD86 in generation and maintenance of functional virus-specific CD8+ T cells in mice infected with lymphocytic choriomeningitis virus.
Grujic Mirjana, Bartholdy Christina, Remy Melissa, Pinschewer Daniel D, Christensen Jan P, Thomsen Allan R (2010), The role of CD80/CD86 in generation and maintenance of functional virus-specific CD8+ T cells in mice infected with lymphocytic choriomeningitis virus., in Journal of immunology (Baltimore, Md. : 1950), 185(3), 1730-43.
T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner.
Pinschewer Daniel D, Schedensack Mariann, Bergthaler Andreas, Horvath Edit, Brück Wolfgang, Löhning Max, Merkler Doron (2010), T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner., in Brain : a journal of neurology, 133(Pt 4), 1054-66.
Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity.
Flatz Lukas, Hegazy Ahmed N, Bergthaler Andreas, Verschoor Admar, Claus Christina, Fernandez Marylise, Gattinoni Luca, Johnson Susan, Kreppel Florian, Kochanek Stefan, Broek Maries van den, Radbruch Andreas, Lévy Frédéric, Lambert Paul-Henri, Siegrist Claire-Anne, Restifo Nicholas P, Löhning Max, Ochsenbein Adrian F, Nabel Gary J, Pinschewer Daniel D (2010), Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity., in Nature medicine, 16(3), 339-45.
T cell-dependence of Lassa fever pathogenesis.
Flatz Lukas, Rieger Toni, Merkler Doron, Bergthaler Andreas, Regen Tommy, Schedensack Mariann, Bestmann Lukas, Verschoor Admar, Kreutzfeldt Mario, Brück Wolfgang, Hanisch Uwe-Karsten, Günther Stephan, Pinschewer Daniel D (2010), T cell-dependence of Lassa fever pathogenesis., in PLoS pathogens, 6(3).
Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions.
Hegazy Ahmed N, Peine Michael, Helmstetter Caroline, Panse Isabel, Fröhlich Anja, Bergthaler Andreas, Flatz Lukas, Pinschewer Daniel D, Radbruch Andreas, Löhning Max (2010), Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions., in Immunity, 32(1), 116-28.
Impaired antibody response causes persistence of prototypic T cell-contained virus.
Bergthaler Andreas, Flatz Lukas, Verschoor Admar, Hegazy Ahmed N, Holdener Martin, Fink Katja, Eschli Bruno, Merkler Doron, Sommerstein Rami, Horvath Edit, Fernandez Marylise, Fitsche André, Senn Beatrice M, Verbeek J Sjef, Odermatt Bernhard, Siegrist Claire-Anne, Pinschewer Daniel D (2009), Impaired antibody response causes persistence of prototypic T cell-contained virus., in PLoS biology, 7(4).
Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors.
Löhning Max, Hegazy Ahmed N, Pinschewer Daniel D, Busse Dorothea, Lang Karl S, Höfer Thomas, Radbruch Andreas, Zinkernagel Rolf M, Hengartner Hans (2008), Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors., in The Journal of experimental medicine, 205(1), 53-61.
Cross-species analysis of the replication complex of Old World arenaviruses reveals two sites in nucleoprotein involved in L protein function.
Kerber Romy, Rieger Toni, Busch Carola, Flatz Lukas, Pinschewer Daniel D, Kümmerer Beate M, Günther Stephan, Cross-species analysis of the replication complex of Old World arenaviruses reveals two sites in nucleoprotein involved in L protein function., in Journal of virology.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Society for Virology (GfV) annual meeting 01.03.2011 Freiburg, Germany
Annual meeting of the German society for immunology (DGFI) 06.09.2010 Leipzig, Germany
NSV2010 conference on negative strand RNA viruses 05.07.2010 Brugge, Belgium
Thinking Out-of-the-Box: Innovative Ideas towards TB Vaccine Discovery 05.04.2010 Annecy
European Congress of Virology 01.04.2010 Cernobbio, Italy
Annual meeting of the Swiss Society for Allergology and Immunology (SSAI), 02.03.2009 Genf
First Swiss Workshop in Fundamental Virology 02.02.2009 Fribourg
Annual meeting of the Swiss Society for Allergology and Immunology (SSAI) 01.03.2008 Fribourg


Awards

Title Year
Pfizer Forschungspreis für Infektiologie, Rheumatologie und Immunologie 2011
Loeffler-Frosch Preis der Gesellschaft für Virologie 2010
Prix Scientifique de la Fondation Leenaards 2010

Associated projects

Number Title Start Funding scheme
135442 Virus-host balance and pathogenesis in persistent infection 01.09.2011 SNSF Professorships
128666 Gamma Irradiator for Research in Immunology, Infectious Diseases, Stem Cell Biology, and Neurobiology 01.12.2009 R'EQUIP

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