InfectX - Systems Biology of Pathogen Entry into Human Cells

Background

The current strategy to fight infectious diseases has focused mainly on targeting unique processes or enzymes of pathogens with specific drugs to eradicate the causative pathogen. The major advantage of this approach is the minimal toxic side effects to the host due to evolutionary divergence between host and pathogen. The most notable examples of this approach are antibiotics and anti-viral drugs. However, despite tremendous success of these drugs in modern medicine, a serious disadvantage of this pathogen- directed strategy has been the rapid development of bacterial and viral drug resistance mechanisms. This has become an increasingly serious problem, requiring the development of more effective vaccines and the identification of novel drug targets that can be used against resistant or mutated microbial pathogens.

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 project 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.

 

Goals

The goal of InfectX is to experimentally identify the human infectome involved in pathogen entry, to reconstruct the topology of the signaling network and derive models of key signaling pathways controlling pathogen entry by iterative cycles of modeling and experimentation, and to explore the inferred models to predict promising drug targets for the development of novel classes of anti‐infectives that block host signaling proteins essential for pathogen entry.


Aims and Approach

  • To use state‐of‐the‐art experimental approaches, i.e. RNAi and proteomics, to systematically identify the human infectome involved in pathogen entry; in particular the subset of human proteins of the model epithelial cell line HeLa that are required for cellular uptake of a representative set of bacterial and viral pathogens.

  • To use an iterative experimental and modeling approach to reconstruct, from the infectome defined above, the topology of the human epithelial cell signaling network controlling pathogen entry as well as mechanistic models of key signaling pathways of  this network that have predictive power.

  • To use RNAi and specific small molecule inhibitors to study the role of central components of the reconstructed human epithelial cell signaling network of pathogen entry in uptake of the studied model pathogens by other human cell types typically infected by intracellular pathogens (e.g. macrophages, dendritic cells, etc.), as well as in entry of other intracellular pathogens of medical importance (e.g. Mycobacteria, HIV, HCM etc.).

  • To predict components of the signaling network that represent promising targets for the development of novel anti‐infectives.