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- Title
A novel experimental model of Cryptococcus neoformans-related immune reconstitution inflammatory syndrome (IRIS) provides insights into pathogenesis.
- Authors
Eschke, Maria; Piehler, Daniel; Schulze, Bianca; Richter, Tina; Grahnert, Andreas; Protschka, Martina; Müller, Uwe; Köhler, Gabriele; Höfling, Corinna; Rossner, Steffen; Alber, Gottfried
- 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.
- Publication
European Journal of Immunology, 2015, Vol 45, Issue 12, p3339
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201545689