Analysis of pathomechanisms of immune reconstitution inflammatory syndrome in Cryptococcus neoformans-infected mice

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Antiretroviral therapy (ART) has yielded major advances in fighting the HIV pandemic. However, a significant medical problem remains to be solved in a number of HIV+ patients co-infected with Cryptococcus neoformans. Upon ART-induced restoration of the immune system this subgroup of patients develops a life-threatening immune reconstitution inflammatory syndrome (IRIS). The mechanisms of the uncontrolled inflammatory response during cryptococcal IRIS are enigmatic. Thus, we recently established a mouse model of cryptococcal IRIS to study disease development. Initial data point to a central role of T helper cells in pathogenesis. The objective of this application is to further refine our model and study the cellular and molecular players of cryptococcal IRIS in depth. The project should result in novel ways to diagnose and predict cryptococcal IRIS. Moreover, targets will be identified for novel therapies which can be tested in this murine model. Together, the proposed study will enable insights in the regulatory mechanisms of inflammatory responses in the immunodeficient as well as immune reconstituting organism.