InfectX - Systems Biology of pathogen entry into human cells

A new line of defense against bacterial and viral infections consists of drugs designed against host proteins that are essential for infection. In order to colonize cells, pathogens subvert the functions of a limited number of host cell receptors, signaling proteins and molecular machines described as the infectome. The aim of the InfectX RTD pro-ject is to comprehensively identify the components of the human infectome for a set of important bacterial and viral pathogens and to develop new mathematical and computational methods with predictive power to reconstruct key signaling pathways controlling pathogen entry into human cells. The components of the infectome will be identified by combining high-content microscopy-based, genome-wide RNA interference (RNAi) screens with surface- and phospho-proteome datasets. Functional and molecular characterization of key signaling components will occur by iterative loops between secondary RNAi screens, biochemistry, multi-dimensional fluorescence microscopy and computational-based pathway reconstruction methods. The refined models will then be used to predict human targets suitable for the development of novel anti-infectives that interfere with pathogen entry into human cells.

Classical infection biology and cellular immunology studies have shown that pathogens subvert many host cell functions to complete their infection cycle. For many human pathogens, these studies have identified several critical pathogenic virulence factors as well as their corresponding host targets. However, these approaches were insufficient to explain and predict the outcome of infections, most likely because of the interactions of several hundred of host/pathogen components. Moreover, while the systematic identification of virulence factors was achievable by performing genetic screens of pathogens, the systematic identification of host factors was only recently made possible by the development of RNAi screens that cover the entire genomic space in mammalian cells. The generation of large datasets, the extensive manipulation of the host and the pathogen as well as the increasing number of bioinformatics tools paved the way towards an integrative approach where the interacting host/pathogen networks are described as,functional units or systems. Such a systems biology approach not only allows the identification of all host/pathogen interacting factors but also to identify the underlying biological
concepts that govern infections. By gaining understanding at the level of the host and pathogen networks and by cross comparing this information between pathogens, we will be in the unique position to decipher common rules and principles that guide bacteria and viruses to become efficient pathogens. Of course, we will use this systems level knowledge to identify host drug targets for anti-infective treatments for which new therapeutic options are currently critically decreasing. This field has been deserted by large pharmaceutical companies and in this context, a joint effort from academia and biotechs may be critical. In collaboration with LipidX and PhosphoNetX, InfectX will give a leading position to SystemsX.ch in the field of infectious diseases in Switzerland and in the world. We hope that this network will work as a nucleation center where additional academic labs and industry partners interested in infections (for instance Actelion) will aggregate in the near future. We will put specific emphasis on the fact that reports on our activities, results protocols are easily browseable and accessible through the web to the scientific community.