Backround and significance

The survival of infectious pathogens depends on their capability to replicate and spread in the infected host. This is influenced by the fitness of the pathogen, the architecture of the target tissue and the balance of general and pathogen-specific host factors that either promote or restrict pathogen replication. Host factors and fitness determinants have been indentified and characterized for many pathogens. However, most studies relied on simplified monolayer cell cultures and qualitative analyses. Quantitative and cross-comparative studies of pathogen replication and spread in more authentic culture systems are lacking.

EcTop 4 aims to close this gap by combining quantitative analyses of pathogen replication and spread at high spatio-temporal resolution with mathematical modeling and by developing and applying culture systems closely mimicking the in vivo situation. Comparative analyses of different pathogens under standardized culture conditions will allow novel insights into similarities and differences.

The central goals of the proposed project are:

i.  To identify common and pathogen-specific principles of pathogen-host cell interaction,

ii.  To establish mathematical models of pathogen replication and spread taking into account the stochastic nature of molecular processes,

iii. To apply these mathematical models to increasingly complex cell culture systems, starting with standard monolayers up to organotypic 3D cultures,

iv. To identify rate-controlling steps of pathogen replication and spread,

v. To exploit these data in order to develop novel, broadly active therapeutic approaches.

 

CellNetworks with its core facilities and infrastructure that were created during the first funding period is particularly qualified to tackle this challenge and provides the necessary expertise in required disciplines including pathogen biology, cell culture models, biophysics, bioinformatics and mathematical modeling. Investigators of the proposed project are experts for the pathogens studied, including HBV, HCV, and HDV (Bartenschlager, V. Lohmann, Schirmacher, Urban), DENV (Bartenschlager), HIV (Fackler, Kräusslich, Müller) and Plasmodium (Frischknecht). The unique collection of pathogen expertise and cell culture systems and the successfully established collaboration on data analysis and mathematical modeling with Z3 (Hamprecht, Höfer, Huber, Kaderali, Schwarz) provides an ideal framework for crosscomparative studies that rely on harmonized and standardized experimental systems.