An underlying viral infection can modulate secondary pathogen encounters in different ways. For instance, virus infections such as HIV or Measles are associated with immunosuppression and enhanced susceptibility to opportunistic infections, resulting in millions of death worldwide. On the other hand, other viruses such as influenza and varicella predispose to exaggerated immune responses that prime the host for severe septic-shock like syndrome upon secondary bacterial encounters. It has been well demonstrated that microbial recognition by toll like receptors (TLRs) on dendritic cells (DCs) determines the magnitude of inflammation, limits early pathogen replication and sets the imprinting of the ensuing adaptive immunity. However, the effect of an ongoing virus infection on DC-TLR signaling and its impact on subsequent pathogen challenges is not as clear. I recently reported that in vivo infection of mice with Lymphocytic choriomeningitis virus (LCMV) differentially modulates subsequent TLR challenges inhibiting TLR3, TLR7 and TLR9 responses and enhancing TLR4 signaling (Zuniga et al. Cell Host &Microbe. 2008). Remarkably, this TLR dysregulation relates to enhanced susceptibility to both murine cytomegalovirus opportunistic infection and lypopolysaccharide endotoxic shock. My overall hypothesis is that DC exposure to the infectious environment alters the normal TLR signaling events leading to an exaggerated response to particular TLRs and suppressed signaling to others. To test this hypothesis I propose to investigate the effect of in vivo LCMV infection on critical events of DC-TLR signaling cascade including uptake and trafficking of TLR ligands, activation of related transcription factors and expression of TLR negative regulators. Furthermore, I will investigate the role of the infectious environment, particularly transforming growth factor beta signaling on DCs, on DC dysfunction during LCMV infection and its impact on primary and secondary virus replication. Uncovering the mechanisms underlying virus diversion of innate immunity may reveal previously unrecognized regulatory pathways and viral strategies to subvert innate response. This new knowledge will help to design therapeutics to prevent and treat secondary infections associated with viral diseases. In addition, LCMV is the prototypic arenavirus and thereby information obtained from this project will help in understanding the pathogenesis of the life threatening human hemorrhagic fever arenaviruses. PUBLIC HEALTH RELEVANCE: Underlying virus infections are responsible for millions of deaths worldwide due to modulation of secondary pathogen encounters including impaired immune response against opportunistic infections (i.e.: HIV or Measles virus). We recently reported that an ongoing viral infection interferes with the ability of dendritic cell (DC) to mount an effective innate response against secondary pathogens. This is a consequence of dysregulated toll like receptor (TLR) responses in DCs and serves for enhanced susceptibility to opportunistic infections. This proposal addresses the mechanisms by which DC-TLR responses are altered during viral infections and thus has the potential to provide novel therapeutic strategies to fight-off opportunistic pathogens associated with viral diseases.