Novel modulation of dendritic cell response against a chronic virus infection

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DESCRIPTION (provided by applicant): Chronically infecting viruses often evade or suppress the host immune system to avoid immunological surveillance and establish persistence in the host. Lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl 13) strain infects the mouse, its natural host, induces profound immune suppression and persists in the host up to 100 days. The immunosuppression caused by LCMV Cl 13 infection is associated with impairment of the most potent antigen-presenting dendritic cell (DC) response in stimulating virus-specific T cells. Thus, LCMV Cl 13 infection serves as an excellent animal model for study of the virus-immune system interaction and viral persistence. The sphingosine is one unit of the sphingolipid group, a bioactive lipid mediator regulating multiple cellular conditions with curative potential for autoimmune diseases. Indeed, the sphingosine analog FTY720 is a promising immunosuppressant that is being tested in phase III clinical trials for the treatment of multiple sclerosis to replace current type I IFN (IFN-2) therapy. However, the sphingosine's mechanism of modulating the host immune response upon chronic virus infection requires further clarification. Preliminary data indicate that, unlike its known immune-suppressive activity, a sphingosine analog stimulates the phenotype and function of DCs upon LCMV Cl 13 infection. The results indicate that sphingosine analogs could reverse chronic viral suppression of the DC response to expand anti-viral T cells. In this proposal, the new immunostimulatory potential of the sphingosine analog directly acting on DCs will be further explored: 1) Adoptive transfer experiments with the sphingosine analog-treated DCs will be employed to further assess the sphingosine analog-mediated regulation of DCs upon LCMV Cl 13 infection. Kinetic study would illuminate the formation and activation of LCMV-specific T cells and viral clearance that are influenced by the sphingosine analog-conditioned DCs; 2) The cytotherapeutic potential of sphingosine analog- treated DCs will be evaluated by using the mouse model of persistent infection with LCMV Cl 13; 3) Further, molecular downstream signaling pathways triggered by the sphingosine analog on DCs will be investigated by evaluating the performance of biochemical and immunological assays. Accordingly, this research is expected to discover novel signaling pathways important for increasing the potency of antigen-presenting DC's capacity and the role of the sphingosine analog in host DC responses to the chronic virus infection. In consequence, the project proposed here should assist in developing novel immuno-therapeutics to remedy chronic viral diseases. PUBLIC HEALTH RELEVANCE: Multiple viruses evade or suppress dendritic cell (DC) responses to establish persistent infections. Recent identification of sphingosine analogs as immune regulators affecting diverse aspects of host immunity prompted us to investigate their role in the DC-mediated host defense and immune responses against a chronic virus infection. Uncovering the mechanisms by which sphingosine analogs stimulate DCs and identifying the analog-triggered intracellular signaling pathways on DCs could provide a basis for the development of novel DC-mediated immunotherapeutic vaccines to conquer persistent viral diseases.