Dissecting immune response to Ebola virus and identifying the fate decisive steps by modelling a cytokine network
The intermittent outbreaks of Ebola virus in West Africa urge a full understanding of the mechanisms by which the virus hampers the immune system in order to design the most effective countermeasures. Although various molecular and cellular mechanisms have been revealed by experimental studies, the systemic roles of these molecular/cellular events in determining the fate of infected human subjects are not clear. Working together with researchers in the Bernhard Nocht Institute for Tropical Medicine in Hamburg, we aim at identifying the key differences and the underlying mechanism between the immune response of survivors and non-survivors. Our approach engages an ODE based model of a cytokine network, which represents key immune mechanisms against viral infections and includes various mechanisms used by the virus in surpassing the immune system. The mathematical model is calibrated by data on immune responses in patients from different outbreaks. Various hypotheses are tested in silico and ranked according to their likelihood. The most likely hypotheses are further used to suggest promising treatment strategies based upon immune modulation as a novel therapeutic target in future outbreaks.
The project also involves the development of novel numerical optimization algorithms for parameter estimation in systems biology applications. Our studies suggest that the innate immune response before symptom onset of non-survivors is slower, than that of survivors. Although this does not lead to significant differences between the type 1 interferon response of the two groups in silico, a slow innate response leads to weaker T cell activation and weaker antibody response, ultimately inducing a higher viral load and increased T cell suppression. The model also suggests that T cells are key in controlling the viral load and that the virus may escape by inducing T cell suppression.
Sebastian Binder, Michael Meyer-Hermann
César Muñoz-Fontela (Bernhard-Nocht-Institut für Tropenmedizin), Georg Pongratz (Universitätsklinikum Düsseldorf), Rainer Straub (Universitätsklinikum Regensburg)
- Systems Immunology- Prof. Dr. Michael Meyer-Hermann