The goal of this project is to identify mechanisms by which the adhesion receptor, PSGL-1 (P-selectin glycoprotein-1) regulates the establishment of a chronic LCMV infection and to assess whether targeting this receptor represents a clinically translational approach to treating chronic viral infections. With more than 500 million people infected with HIV, HCV, and HBV worldwide, chronic viruses represent a major global health problem. The murine model of chronic LCMV infection has been widely demonstrated to have clinical relevance to human chronic infections. Although numerous anti-viral compounds and biologicals can inhibit viral replication, current therapies are associated with significant toxicity and/or immunopathology. It is therefore critically important to develop new targets for treat these infections. Of significance, our studies suggest that ligation PSGL-1 on T cells may be a pivotal event that limits the effector T cell accumulation and leads to dysfunctional virus-specific T cell responses that underlie chronic viral infections. Our data show that the chronic LCMV virus (Clone 13/Cl 13) is unable to establish chronicity in mice that are genetically deficient in PSGL-1, a major receptor for the selectin family of adhesion molecules (P, E, and L). Instead, there are dramatic increases in the numbers of virus-specific CD8+ T cells, deletion of virus-specific T cells is curtailed, and persisting anti-viral T cells fail to develop the exhausted phenotype characterized by sequential loss of effector functions. Virus-specific T cells from PSGL-1 KO mice express greatly reduced levels of immune inhibitory receptors, resulting in enhanced CD8+ T cell functional responses during chronic infection. In addition, the absence of PSGL-1 also supports enhanced virus-specific CD4+ T cell responses to LCMV Cl 13. Most notably, the preservation T cell functionality is associated with viral clearance and severe immunopathology, highlighting a critical function for PSGL-1 as an immune regulator during chronic infection. The data show that there is a broad impact of PSGL-1 on T cell chronic anti-viral responses and support the hypothesis that PSGL-1 is a previously unknown key to negative regulation of T cell immune function. On the basis of our findings we propose to investigate the mechanisms engaged by PSGL-1 to limit anti-viral immunity and explore therapeutic approaches to target this receptor to enhance anti-viral effector T cell responses.

Public Health Relevance

Our studies show that an adhesion molecule expressed on T lymphocytes, PSGL-1 (P-selectin glycoprotein-1) inhibits the immune response to viruses. Blocking its function could provide a new therapeutic approach to treat chronic viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106895-01A1
Application #
8697867
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Park, Eun-Chung
Project Start
2014-09-05
Project End
2018-08-31
Budget Start
2014-09-05
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$487,500
Indirect Cost
$237,500
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037