Project TP 7

(U. Klingmüller/ J. Timmer)

Addressing the multi-factorial impact on viral persistence by integrative dynamic pathway modeling

The liver environment can be critical for at least two different steps in an infectious disease: at the time of infection and early antiviral response or later when a chronic disease has developed. For instance, HCV infection causes liver inflammation, which in turn leads to the secretion of factors inducing liver regeneration, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and hepatocyte growth factor (HGF). Both, the time of secretion of each single factor and the interplay between these factors can critically influence the outcome of the antiviral response. A successful antiviral response is not an isolated event, but involves complex interactions between different cells involving many factors. This might occur by a direct influence on viral replication or by regulation of IFN-alpha signaling in a positive or negative manner. To unravel these mechanisms it is critical to examine the complex interplay of the involved components and to consider the dynamics of the process.

Therefore, the Klingmüller and Timmer group will employ a systems biology approach to examine, with the help of mathematical modeling, the dynamic interplay of different factors present in the liver and their impact on anti-viral responses. Mathematical models allow to analyze and to integrate complex interactions of different components over time, which is not possible with a traditional approach. Moreover, these models can be used for optimal experimental design and rapid generation of hypotheses. An important prerequisite for this approach is the generation of time-resolved quantitative data suitable for mathematical modeling. Hence, in close collaboration with the other partners, standard operating procedures for the cultivation and propagation of cell lines and primary cells will be developed. Furthermore, similar to the advancements in quantitative immunoblotting, the Klingmüller and Timmer groups will establish strategies for reliable determination of absolute values obtained with protein arrays and the multiplex bead based technology, and for storing and exchanging experimental data. In iterative steps an integrative mathematical model will be established that links IFN-alpha induced signaling with HCV propagation and considers the impact of inflammatory cytokines such as IL-6, TNF-alpha, TGF-beta as well as the effect of proliferative stimuli in the liver exerted e.g. by HGF. The dynamics of pathway activation in uninfected and HCV infected cells will be monitored by quantitative immunoblotting, the multiplex bead based technology and quantitative protein-arrays, which will be complemented by time-resolved analysis of target gene induction using qRT-PCR and microarrays. The integrative data-based mathematical model will facilitate the prediction of strategies for targeted perturbation in order to enhance the efficiency of antiviral responses and to prevent persistent infection with HCV.
© Dep. of Infectious Diseases, Molecular Virology. University of Heidelberg
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