title: A novel experimental model of Cryptococcus neoformans-related immune reconstitution inflammatory syndrome (IRIS) provides insights into pathogenesis.
abstract: Antiretroviral therapy (ART) has yielded major advances in fighting the HIV pandemic by restoring protective immunity. However, a significant proportion of HIV patients co-infected with the opportunistic fungal pathogen Cryptococcus neoformans paradoxically develops a life-threatening immune reconstitution inflammatory syndrome (IRIS) during antiretroviral therapy. Despite several clinical studies, the underlying pathomecha-nisms are poorly understood. Here, we present the first mouse model of cryptococcal IRIS that allows for a detailed analysis of disease development. Lymphocyte-deficient RAG-1(-/-) mice are infected with C. neoformans and 4 weeks later adoptively transferred with purified CD4(+) T cells. Reconstitution of CD4(+) T cells is sufficient to induce a severe inflammatory disease similar to clinical IRIS in C. neoformans-infected RAG-1(-/-) mice of different genetic backgrounds and immunological phenotypes (i.e. C57BL/6 and BALB/c). Multiorgan inflammation is accompanied by a systemic release of distinct proinflammatory cytokines, i.e. IFN-γ, IL-6, and TNF-α. IRIS development is characterized by infection-dependent activation of donor CD4(+) T cells, which are the source of IFN-γ. Interestingly, IFN-γ-mediated effects are not required for disease induction. Taken together, this novel mouse model of cryptococcal IRIS provides a useful tool to verify potential mechanisms of pathogenesis, revealing targets for diagnosis and therapeutic interventions.
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Eschke
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Piehler
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Schulze
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Richter
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Grahnert
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Protschka
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Müller
authors.affiliation: Institute for Pathology, Klinikum Fulda gAG, Fulda, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.affiliation: Paul Flechsig Institute for Brain Research, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Höfling
authors.affiliation: Paul Flechsig Institute for Brain Research, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rossner
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Alber
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D003453:Cryptococcosis / Q000150:complications*; D003455:Cryptococcus neoformans; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000502:physiology; D054019:Immune Reconstitution Inflammatory Syndrome / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein
keywords: CD4+ T cells; Cryptococcus neoformans; Fungal immunity; Immune reconstitution; Inflammation