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: Maria Eschke, Daniel Piehler, Bianca Schulze, Tina Richter, Andreas Grahnert, Martina Protschka, Uwe Müller, Gabriele Köhler, Corinna Höfling, Steffen Rossner, Gottfried Alber
• Journal: European journal of immunology (Eur J Immunol) Vol. 45 Issue 12 Pg. 3339-50 (Dec 2015) ISSN: 1521-4141 [Electronic] Germany
• PMID: 26381487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Homeodomain Proteins
• RAG-1 protein

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• Cell Movement
• Cryptococcosis (complications)
• Cryptococcus neoformans
• Disease Models, Animal
• Homeodomain Proteins (physiology)
• Immune Reconstitution Inflammatory Syndrome (etiology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL