Modeling the Proinflammatory Microenvironment and Immune Response Dynamics During Infection

Intracellular pathogens like Francisella tularensis (Ft), a gram-negative Class A biothreat agent can trigger the release of cytokines, chemokines, and effector molecules into the microenvironment surrounding the infected cell, contributing to the formation of a proinflammatory microenvironment (PME). Immune cells recruited into the PME can be primed and activated by cytokine exposure promoting a more robust interaction between infiltrating immune cells and infected cells or, in the case of phagocytic cells, priming the cell to more effectively eliminate subsequent Ft infection. Macrophages and NK cells are central to the innate immune response to Ft and primary producers of TNF-α and IFN-γ, respective. Focusing on these key PME cytokines, which are found to modulate the in vivo response to Ft, we developed in silico and in vitro models to investigate the role of PME in macrophage activation and outcome of infection. Our results suggest that TNF-α priming does not significantly change the dynamics of Ft infection response, whereas IFN-γ priming significantly enhances the inflammatory response by up-regulating the macrophage effector response, endogenous TNF-α production, and the anti-inflammatory cytokine, IL10.