(464f) Quantitative Virus-Host Interactions: Toward Cross-Validated Measures of Cell Signaling Responses to Virus Infection

Viruses are of great biomedical importance, as their infections cause a variety of major diseases including influenza, SARS, AIDS, hemorrhagic fevers, and diarrhea. Viral pathogenesis depends on the interplay between virus replication and spread and the function of the immune system. The earliest and most essential host responses to acute viral infections are through the innate immune system, a complex signaling network triggered by presence of viral-associated molecules such as double-stranded RNA. While the spread of infection in susceptible hosts is a major indicator of viral pathogenesis, it is increasingly recognized that host immune responses can also play a crucial role in pathogenesis. Highly pathogenic strains of influenza, for example, trigger an uncontrolled innate immune response known as a ?cytokine storm? that leads to inflammation and tissue damage. This phenomenon appears to be caused by an unknown feedback mechanism within the innate immune system.

Positive feedback within the innate immune system arises from a number of mechanisms, including viral proteins that enable their own amplification (viral polymerases) and host signaling proteins that amplify their own expression while triggering downstream anti-viral effects (e.g. interferons). Additionally, viruses have evolved numerous mechanisms to block aspects of immune signaling to increase their ability to successfully replicate. The complexity of this system has prevented the elucidation of the signaling network and feedback phenomena, and presents a clear candidate for a Systems Biological approach.

Models of the innate immune system are currently limited by lack of relevant experimental data. We use a multipronged approach to collect quantitative, kinetic data for viral and signaling proteins, using LC coupled mass spectrometry, sandwich ELISA and blotting to create comprehensive and cross-validated data sets specifically intended for modeling. Our model system is Vesicular Stomatitis Virus, a simple, well-characterized virus grown on baby hamster kidney and human prostrate cancer cell lines. Our data sets will be used to create models of the innate immune system to elucidate the signaling networks inherent in the system. These models will be relevant to antiviral drug design, immunological research and virus-based anti-cancer therapies.