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Innate Immune Mechanisms and T-Cell Responses to Equine Herpesvirus Type 1 in Latently Infected and Naive Horses

Principal Investigator: Bettina Wagner

Co-PI: Gillian Perkins

Department of Population Medicine and Diagnostic Sciences
Sponsor: Harry M. Zweig Memorial Fund for Equine Research
Title: Innate Immune Mechanisms and T-Cell Responses to Equine Herpesvirus Type 1 in Latently Infected and Naive Horses
Project Amount: $173,529
Project Period: January 2013 to December 2014

DESCRIPTION (provided by applicant): 

Equine herpesvirus type 1 (EHV-1) outbreaks continue to occur in the US despite the wide use of vaccination.  Although disease outbreaks have been rapidly detected and were professionally managed to prevent wider distribution of disease, a more effective EHV-1 vaccine is needed to reduce the impact of this virus on equine health and economic losses in the equine industry.  The long-term goal of our group is to identify specific EHV-1 genes as new targets for vaccines that improve adaptive cellular immunity in horses.  Adaptive cellular immunity, and in particular T-cell immunity, is considered to provide protection against EHV-1.  Current vaccines were shown to induce robust humoral immunity (antibody responses) but fail or are of low efficacy in providing cellular adaptive immunity.  Existing vaccines clearly helped to decrease respiratory disease and abortion storms in horses.  However, they largely failed in preventing the repeated severe neurological outbreaks we have faced in the US during the past few years.

In the project preceding this proposal, we investigated immune modulating effects of different EHV-1 genes on equine peripheral blood cells in vitro.  In collaboration with Dr. Osterrieder’s group in Berlin, we designed deletion mutants of EHV-1 that were lacking specific viral genes (e.g. ORF1/2, UL49.5, or ICP0).  The EHV-1 deletion mutants were then cultured with equine blood cells to evaluate their in vitro effects on innate cellular immunity and EHV-1 specific T-cell stimulation.  All three genes significantly modified cellular immune responses to EHV-1 and induced less ‘danger signals’ (type I interferon and chemokine responses) compared to the wild type EHV-1 strain.  High induction of adaptive T-cell immunity was observed for the ORF1/2 deletion mutant.  ORF1/2 genes of EHV-1 are expected to alter antigen-presentation.  T-cell initiation depends on the antigen-presentation process.  Therefore, we developed the hypothesis that the deletion of the ORF1/2 genes from the EHV-1 virus is likely to improve T-cell immunity, protection against EHV-1 and severe disease induced by current EHV-1 strains.

In this project, we propose to analyze in vivo whether the ORF1/2 deletion mutant indeed induces increased adaptive cellular immunity and protection against EHV-1 in horses (Aim 1).  We will also continue to analyze the underlying immune principles that lead to the observed immune activation by EHV-1 deletion mutants with focus on ORF1/2 (Aim 2).  To perform this project, our team of investigators includes EHV-1 experts from various disciplines: Dr. Perkins (Large Animal Internist, Co-PI) will be responsible for all clinical aspects of this project.  As collaborators on this project, Drs. Osterrieder (Virologist and world-leading EHV-1 expert) and Dr. Van der Walle (Virologist and well established young investigator in EHV-1 research) will contribute with expertise, specific tools and methods to the virologic parts of the project.  Dr. Wagner (Immunologist, PI) will oversee the project and will be responsible for all immunologic aspects of the study.  Dr. Van der Walle will join the Baker Institute faculty as an Assistant Professor in January 2013.  Dr. Wagner’s and Dr. Osterrieder’s group have worked collaborative on EHV-1 research during the past five year, i.e. while Dr. Osterrieder was still at Cornell and since he is in Berlin, Germany.

To perform Aim 1 of this project, we will use horses from our SPF-herd originating from Iceland.  This herd is currently kept at Cornell and provides a unique group of horses that have not been previously exposed to EHV-1.  EHV-1 and many other common US horse pathogens do not exist in Iceland.  The herd is kept under specific restrictions (access only for project associated personnel, no contact to other horses, etc.) at Cornell to maintain the EHV-1 negative status.  The EHV-1 status (humoral and cellular immunity) of the animals is constantly monitored.

The immediate goal of this project is to provide proof-of-principle for the efficacy of a new vaccine candidate (Ab4ΔORF1/2) for EHV-1.  Based on our accumulated immunological data from in vitro studies during the past few years, the Ab4ΔORF1/2 deletion mutant is a very promising EHV-1 vaccine candidate with a clear potential to lead to protection against neurological disease (myeloencephalopathy) and, in the long-term, an overall better protection against EHV-1 in the horse population.

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