Systems approach to investigating host-pathogen interactions in infections with the biothreat agent Francisella. Constraints-based model of Francisella tularensis.
BACKGROUND
Francisella tularensis is a prototypic example of a pathogen for which few experimental datasets exist, but for which copious high-throughout data are becoming available because of its re-emerging significance as biothreat agent. The virulence of Francisella tularensis depends on its growth capabilities within a defined environmental niche of the host cell.


RESULTS
We reconstructed the metabolism of Francisella as a stoichiometric matrix. This systems biology approach demonstrated that changes in carbohydrate utilization and amino acid metabolism play a pivotal role in growth, acid resistance, and energy homeostasis during infection with Francisella. We also show how varying the expression of certain metabolic genes in different environments efficiently controls the metabolic capacity of F. tularensis. Selective gene-expression analysis showed modulation of sugar catabolism by switching from oxidative metabolism (TCA cycle) in the initial stages of infection to fatty acid oxidation and gluconeogenesis later on. Computational analysis with constraints derived from experimental data revealed a limited set of metabolic genes that are operational during infection.


CONCLUSIONS
This integrated systems approach provides an important tool to understand the pathogenesis of an ill-characterized biothreat agent and to identify potential novel drug targets when rapid target identification is required should such microbes be intentionally released or become epidemic.
Raghunathan
Anu
A
Mount Sinai School of Medicine, Department of Medicine, One Gustave L, Levy Place, New York, NY 10029, USA.
Shin
Sookil
S
Daefler
Simon
S
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D054045:Biological Warfare Agents; D002244:Carbon / Q000494:pharmacology; D005604:Francisella tularensis / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D020869:Gene Expression Profiling; D005798:Genes, Bacterial / Q000235:genetics; D054884:Host-Pathogen Interactions; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D049490:Systems Biology / Q000379:methods*; D014406:Tularemia / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D054045:Biological Warfare Agents; D002244:Carbon