virus (VSV), and use this information to design more effective, safer recombinant live virus vaccines againstYersinia pestis and pox viruses. Previous strategies for attenuating pathogenesis of recombinant VSVvaccine vectors have focused on reducing the ability of the virus to produce infectious progeny. This has theI The goal of this project is to identify the mechanisms that account for pathogenesls of vesicular stomatitisundesired effect of reducing the level of antigen expression and reducing the subsequent immune response.In contrast, we have developed a new strategy for attenuating viral pathogenesis by reducing theability of the virus to suppress host innate immune responses without compromising the yield ofinfectious progeny or the level of antigen expression from infected cells.These vectors are designedto have greater efficacy by enhancing innate immune mechanisms and greater safety by modifying thedeterminants of viral pathogenesis.
Aim 1 is to determine the pathogenesis and cytokine production by VSVvectors that activate innate immune mechanisms. These experiments involve analysis of virus disseminationand cytokine production in mice infected with recombinant M protein mutant viruses, which fail to suppresshost innate immune responses, and recombinant viruses that express Salmonella flagellin as an activator oftoll-like receptors responsible for induction of innate immune responses.
Aim 2 is to test the hypothesis thatactivation of innate immune mechanisms by mutant viruses leads to more effective adaptive immuneresponses. The ability of recombinant mutant VSV vectors to elicit antibodies against a bacterial pathogenand to protect against bacterial challenge will be tested using vectors that express the F1 and V antigens ofY. pestis. The ability of these vectors to elicit cytotoxic T lymphocytes and protect against respiratorychallenge with poxviruses will be tested using vectors that express surrogate antigens expressed byrecombinant vaccinia viruses. These experiments address directly the dilemma faced in developingattenuated viruses as vaccines: a virus that is too attenuated for growth will not elicit a very effective immuneresponse, while one that is not attenuated enough will be unsafe. In contrast, a virus that is attenuated bybeing unable to suppress the host response may be a more effective and safer vaccine.
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