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Impact of chronic liver inflammation on adaptive immune responses to viral infection

dc.contributor.advisorGarbi, Natalio
dc.contributor.authorAssmus, Lisa Mareike
dc.date.accessioned2020-04-27T20:44:26Z
dc.date.issued11.03.2020
dc.identifier.urihttp://hdl.handle.net/20.500.11811/8331
dc.description.abstractA common complication in patients suffering from chronic liver inflammation and fibrosis is the enhanced susceptibility to viral infections and weak responses to vaccination, which are associated with significant co-morbidities. To unravel the cellular and molecular mechanisms underlying the impaired adaptive immune response during liver fibrosis, we investigated the T cell-mediated immune responses to lymphocytic choriomenigitis virus (LCMV) infection, as well as in response to OVA/PolyI:C vaccination. Using the bile duct ligation (BDL) murine model of chronic liver inflammation and fibrosis, we found that chronic liver damage is associated with persistence of infection, recapitulating the clinical situation in humans. Hallmarks of the defective anti-viral immunity in these mice were reduced expansion of LCMV-specific CD4+ and CD8+ T cells, decreased expression of IFNγ and TNFα, as well as an elevated co-expression of the exhaustion marker PD1 together with LAG3 and TIM3 in virus-specific T cells from the spleen and liver. The reduced number of LCMV-specific CD4+ and CD8+ T cells are due to decreased proliferation as well as increased apoptosis among SMARTA T cells. Additionally, LCMV-specific CD4+ and CD8+ T cells display reduced mitochondrial fitness, characterized by a higher proportion of cells containing depolarized (i.e. dysfunctional) mitochondria, and producing high levels of superoxide among SMARTA and P14 T cells from mice with liver fibrosis. After OVA/PolyI:C vaccination antigen-specific CD4+ and CD8+ T cells were similarly reduced in numbers in mice with liver fibrosis and displayed reduced production of IFNγ, TNFα and IL-2. Interestingly, endogenous OVA-specific CD8+ T cells, as well as transferred OT-I T cells also show severe signs of exhaustion after vaccination, which manifested in elevated levels and co-expression of PD-1 and LAG3, as well as PD-1 and TIM3 in mice with liver fibrosis. The future goal of this project is to identify key molecular pathways induced by chronic liver damage that can be therapeutically modulated to promote anti-viral immunity and to improve vaccination responses in patients suffering from chronic liver inflammation and fibrosis.
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subject.ddc500 Naturwissenschaften
dc.subject.ddc570 Biowissenschaften, Biologie
dc.subject.ddc610 Medizin, Gesundheit
dc.titleImpact of chronic liver inflammation on adaptive immune responses to viral infection
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsembargoedAccess
dc.date.embargoEndDate2021-03-15
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-57718
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.affiliation.otherLocation1Melbourne
ulbbnediss.affiliation.otherName1University of Melbourne
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID5771
ulbbnediss.date.accepted2020-01-07
ulbbnediss.instituteMedizinische Fakultät / Institute : Institut für Experimentelle Immunologie (IEI)
ulbbnediss.fakultaetMedizinische Fakultät
dc.contributor.coRefereeLa Gruta, Nicole
ulbbnediss.contributor.orcidhttps://orcid.org/0000-0002-4859-8334


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