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Background : Cell mediated immunity ( CMI ) is critical for clearance of intracellular pathogens. Viral persistence can be in part a result of a dysfunctional CMI response. Causes of CMI dysfunction can be attributed to the pathogen, the immune environment and specific lymphocyte properties. Understanding CMI dysfunction during chronic viral infections will lead to ( i ) targeted therapies for the ongoing infection; ( ii) an understanding of mechanisms to maintain immune function within a chronic state for efficient vaccine delivery and the ability to respond to secondary infections; and (iii) immune adjuvant design for alternative and therapeutic vaccine delivery.

Studying a natural model of viral persistence, lymphocytic choriomeningitis virus (LCMV), in mice we can compare a productive immune response generated during infection with the acute Armstrong strain of the virus to a dysfunctional immune response generated during infection with the persistent clone 13 strain. These comparisons have led to the discovery of differences in the early trafficking of naïve T cells during infection. In mice infected with persistent LCMV the immune modulating drug FTY720 was used to force a similar circulation pattern detected during the acute Armstrong infection. We discovered that transient FTY720 treatment of mice at the time of persistent clone 13 infection or during the persistent stage of clone 13 infection reversed a dysfunctional immune response leading to clearance of the infection.

Our laboratory is interested in understanding the mechanism of reversing a dysfunctional CMI response during persistent clone 13 infections at the molecular, cellular and tissue level.

Major goals :

• To understand the reversion of a dysfunctional immune response following FTY720 treatment of clone 13 infected mice.
• Identifying the receptor(s) required for FTY720 mediated restoration of the immune response.
• The role of CD4 + T cells in the reversion of CD8 + T cell function.
• Alterations in the function and location of antigen presenting cells during FTY720 treatment.
• Overall lymphoid and peripheral tissue micro architecture following treatment of clone 13 infected mice with FTY720.
• Characterize the differences in the immune environment over the course of infection with acute LCMV or chronic LCMV focusing on immune architecture, location of immune cells, and cytokine production and chemokine expression in tissues.
• Study how different immune environments affect the ability of bystander naïve T cells to respond to their cognate antigen.
• Develop adjuvants to enhance immunity against weak vaccine antigens that do not invoke a robust innate immune response.