(431h) Epithelial Interferon Production Rates Drive Differential Strain-Specific Immunodynamics

While the in vivo immunodynamics associated with low pathogenic H1N1 and high pathogenic H5N1 strains of influenza A virus display differential behavior, the root cause of these differences remains unknown. Clinically, high pathogenic strains lead to higher rates of morbidity and mortality resulting from an aggressive inflammatory cytokine response. The relationship between type-I interferon, a key warning signal of the early, the innate immune response, and viral replication rate is of interest in determining the differential mechanisms driving strain-specific behavior. In order to better understand and treat various strains of influenza, it is important to determine which aspects of the immune system are behaving differently in different infections.

We used Markov chain Monte Carlo parameterization and simplified models of lung immunity to compare immune responses between low pathogenic, seasonal H1N1 and high pathogenic H5N1 influenza viruses in mice. The model, representative of the innate response days 0-5, contains three states: virus, interferon, and MCP1/macrophage infiltration. The hypothesis driving the design of our study is that most host parameters should be the same for each infection cohort but virus-specific parameters should differ. We developed a customized parameterization routine which enabled us to rapidly create and parameterize an ensemble of models, with each model setting different requirements on which parameters should be equal in the two populations. The AIC was used to compare the quality of each parameterization to account for the varying number of shared parameters across strains. Strain-dependent estimation of the production rate of interferon yields the optimal fit of the parameterizations explored, suggesting that host dynamics may be at the root of observed differences. Comparing the rankings of error and AIC reveals that while independent estimation of all parameters across strains results in the lowest error values, the cost incurred by the additional degrees of freedom is high resulting in the lowest AIC ranking. Biologically, this suggests that mechanistic differences in the host immune response are minimal in number. Together, results point to interferon production rates as the main contributor of strain-specific immunodynamics and serve as a prototype for further comparative studies.