The Immune Response to Vaccinia Virus Infection: Inflammatory Monocytes, Leukotrienes, and CD8+ T Cell Immunodominance
Open Access
- Author:
- Fischer, Matthew Anthony
- Graduate Program:
- Microbiology and Immunology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 14, 2009
- Committee Members:
- Christopher Charles Norbury, Dissertation Advisor/Co-Advisor
Christopher Charles Norbury, Committee Chair/Co-Chair
David A Antonetti, Committee Member
Neil David Christensen, Committee Member
Todd Schell, Committee Member
David Joseph Spector, Committee Member
John Warren Wills, Committee Member - Keywords:
- immunodominance
leukotrienes
inflammatory monocytes
Vaccinia virus
dendritic cell migration - Abstract:
- Although Vaccinia virus (VACV) has been used extensively as a vaccine to convey protection against other poxviruses and, through the expression of recombinant antigens, other pathogens and tumors, several problems exist that limit its potential use within the human population. Two such problems are the dangerous complications of uncontrolled viral replication and the immunodominance of VACV-specific CD8+ T cells. The immune mechanisms responsible for controlling VACV replication at the site of infection were previously unclear. Although adaptive immunity is often given credit for this function, viral titers begin to lower during the innate immune response. Through in vivo cellular depletions, we demonstrated that inflammatory monocytes, including a Ly6C+Ly6G+ subpopulation, are critical factors for controlling VACV replication at the site of infection, preventing spread of the virus to other sites, and limiting immune-mediated tissue damage. Leukotrienes are potent mediators of the innate immune response capable of affecting the monocytic response, although their precise functions in the skin and in viral infections are poorly understood. In MRP1 knockout mice, we observed exacerbated inflammation and tissue damage during an intradermal VACV infection. These effects were not due to a lack of cysteinyl leukotrienes as the use of a cysteinyl leukotriene receptor antagonist alleviated tissue damage. Rather, increased leukotriene B4 levels in MRP1 knockout mice were responsible. When recombinant VACV constructs are utilized to induce CD8+ T cells specific for a recombinantly encoded foreign antigen, the majority of the CD8+ T cell response is directed against VACV. We utilized UV and psoralen treatment to globally reduce the expression of native VACV genes while relatively maintaining the expression of a recombinant antigenic peptide. This increased the primary CD8+ T cell response specific for the recombinant antigen, while decreasing VACV-specific CD8+ T cells. Our findings have implications for the safe and effective use of VACV as a human vaccine. By therapeutically targeting monocytes and/or leukotrienes, the innate immune response can be manipulated to improve the safety of VACV immunization. Further, UV/psoralen treated recombinant VACV constructs represent more effective vaccine vectors for inducing antigen-specific CD8+ T cells.