Dr. Bettina Wagner
Vaccines to equine herpesvirus 1 (EHV-1) induce strong antibody responses but offer only partial protection. Thus, this virus still presents a significant medical and economic burden. The successful initiation of the innate immune response is essential to improve existing, or to develop new more effective vaccines to EHV-1 for the avoidance of neurological EHV-1 outbreaks. According to current knowledge, an improved, protective EHV-1 vaccine needs to increase adaptive cellular immunity. Our data from the Zweig project preceding this renewal application showed that EHV-1 modulates chemokine and cytokine expression. We also found that the potential to down-regulate the innate immune response is higher in neurogenic than in abortogenic EHV-1 strains.
Here, we hypothesize that the ability of the neurogenic EHV-1 Ab4 strain to down-regulate innate immune responses negatively correlates with the development of protective, adaptive T cell immunity and that infection with Ab4 reduces T cell responses and increases the risk of EHV-1 viremia and susceptibility to neurological disease. We further hypothesize that latent EHV-1 infection negatively impacts innate immunity and, after re-infection or virus re-activation, results in increased susceptibility to neurological disease in older horses compared to foals and young horses.
In Aim 1 of this proposal we will target two EHV-1 genes, ICP0 and ORF1/2, that were implicated to modify the host immune response to herpesviruses and thereby contributed to pathogenicity. We will use ICP0 and ORF1/2 deletion mutants of Ab4 in comparison to the wild-type strain and test whether ICP0 or ORF1/2 are re-storing the down-regulation of chemokines and cytokines during the innate immune response. We will further test how the Ab4 mutants and different EHV-1 wild-type strains influence the development of protective adaptive immune responses by performing T cell re-stimulation assays and by analyzing T cell differentiation.
Aim 2 is to analyze the innate immune response to EHV-1 in young and adult horses that have not previously been exposed to EHV-1 in comparison to latently infected horses. PBMC will be isolated and the cells will be infected with different EHV-1 strains. Innate immune responses will be measured (chemokines and cytokines) and compared between non-exposed and latently infected horses.
The objectives of the proposed project are (1) to further improve the understanding of innate immunity in response to EHV-1 infection, (2) to detect differences in abortogenic and neurogenic EHV-1 strains that affect adaptive immunity and T cell function, (3) to identify ‘markers’ of protective immunity, and (4) to find EHV-1 genes that decrease protective cellular immunity.