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1. Intranasal IgG4/7 antibody responses protect horses against equid herpesvirus-1 (EHV-1) infection including nasal virus shedding and cell-associated viremia.

Author

Perkins, Gillian, Babasyan, Susanna, Stout, Alison E., Freer, Heather, Rollins, Alicia, Wimer, Christine L., and Wagner, Bettina

Subjects
*VIRAL shedding, *ANTIBODY formation, *HORSES, *VIRAL antibodies, *INFECTION prevention, *EPITHELIAL cells, *HORSE training
Abstract

Equid herpesvirus-1 (EHV-1) outbreaks continue despite widely used vaccination. We demonstrated previously that an ORF1/ORF71 gene deletion mutant of the EHV-1 strain Ab4 (Ab4ΔORF1/71) is less virulent than its parent Ab4 virus. Here, we describe the Ab4 challenge infection evaluating protection induced by the Ab4ΔORF1/71 vaccine candidate. Susceptible control horses developed respiratory disease, fever, nasal shedding, and viremia. Full protection after challenge infection was observed in 5/5 previously Ab4 infected horses and 3/5 Ab4ΔORF1/71 horses. Two Ab4ΔORF1/71 horses developed short-lasting viremia and/or virus shedding. Protective immunity in the respiratory tract was characterized by pre-existing EHV-1-specific IgG4/7 antibodies, the absence of IFN-α secretion and rapidly increasing IgG4/7 upon challenge infection. Pre-existing systemic EHV-1-specific IgG4/7 highly correlated with protection. T-cell immunity was overall low. In conclusion, protective immunity against EHV-1 infection including prevention of viremia was associated with robust systemic and intranasal IgG4/7 antibodies suggesting immediate virus neutralization at the local site. • ORF1/ORF71 gene deletion from the EHV-1 strain Ab4 reduces virulence and induces similar protection as parent Ab4 virus. • Susceptible horses secrete high amounts of intranasal IFN-a, CCL2, or sCD14 during EHV-1 shedding. • Missing IFN-a, CCL2, and sCD14 secretion at the nasal infection site points to lack of EHV-1 entry into epithelial cells. • Protective host immunity is linked to existing intranasal EHV-1-specific IgG4/7 antibodies suggesting virus neutralization. • High serum IgG4/7 antibodies are robust correlates of protection from disease, EHV-1 shedding and viremia. [ABSTRACT FROM AUTHOR]

Published
2019
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2. The deletion of the ORF1 and ORF71 genes reduces virulence of the neuropathogenic EHV-1 strain Ab4 without compromising host immunity in horses

Author

Bettina Wagner, Susanna Babasyan, Gillian A. Perkins, Alicia Rollins, Alison E. Stout, Christine L. Wimer, Christiane L. Schnabel, Heather Freer, Amy L. Glaser, Nikolaus Osterrieder, and Laura B. Goodman

Subjects
0301 basic medicine, Male, Cellular immunity, Viral Diseases, Pulmonology, Physiology, lcsh:Medicine, Antibody Response, Antibodies, Viral, Biochemistry, Body Temperature, 0403 veterinary science, Random Allocation, White Blood Cells, Interferon, Animal Cells, Immune Physiology, Medicine and Health Sciences, lcsh:Science, Immune Response, Mammals, ORF1, Immunity, Cellular, Innate Immune System, Multidisciplinary, Immune System Proteins, Virulence, T Cells, Eukaryota, 04 agricultural and veterinary sciences, Herpesviridae Infections, Isotype, Virus Shedding, Infectious Diseases, Vertebrates, Cytokines, Female, Antibody, Cellular Types, medicine.drug, Herpesvirus 1, Equid, Research Article, 040301 veterinary sciences, Immune Cells, Equines, Immunology, Viremia, Biology, Nose, Virus, Antibodies, 03 medical and health sciences, Viral Proteins, Immune system, Immunity, medicine, Animals, ORF71, Horses, Secretion, Blood Cells, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Cell Biology, Molecular Development, medicine.disease, Virology, neuropathogenic EHV-1 strain Ab4, 030104 developmental biology, Immunoglobulin G, Immune System, Mutation, Amniotes, Respiratory Infections, biology.protein, lcsh:Q, Horse Diseases, Physiological Processes, Developmental Biology
Abstract

The equine herpesvirus type 1 (EHV-1) ORF1 and ORF71 genes have immune modulatory effects in vitro. Experimental infection of horses using virus mutants with multiple deletions including ORF1 and ORF71 showed promise as vaccine candidates against EHV-1. Here, the combined effects of ORF1 and ORF71 deletions from the neuropathogenic EHV-1 strain Ab4 on clinical disease and host immune response were further explored. Three groups of EHV-1 naive horses were experimentally infected with the ORF1/71 gene deletion mutant (Ab4ΔORF1/71), the parent Ab4 strain, or remained uninfected. In comparison to Ab4, horses infected with Ab4ΔORF1/71 did not show the initial high fever peak characteristic of EHV-1 infection. Ab4ΔORF1/71 infection had reduced nasal shedding (1/5 vs. 5/5) and, simultaneously, decreased intranasal interferon (IFN)-α, interleukin (IL)-10 and soluble CD14 secretion. However, Ab4 and Ab4ΔORF1/71 infection resulted in comparable viremia, suggesting these genes do not regulate the infection of the mononuclear cells and subsequent viremia. Intranasal and serum anti-EHV-1 antibodies to Ab4ΔORF1/71 developed slightly slower than those to Ab4. However, beyond day 12 post infection (d12pi) serum antibodies in both virus-infected groups were similar and remained increased until the end of the study (d114pi). EHV-1 immunoglobulin (Ig) G isotype responses were dominated by short-lasting IgG1 and long-lasting IgG4/7 antibodies. The IgG4/7 response closely resembled the total EHV-1 specific antibody response. Ex vivo re-stimulation of PBMC with Ab4 resulted in IFN-γ and IL-10 secretion by cells from both infected groups within two weeks pi. Flow cytometric analysis showed that IFN-γ producing EHV-1-specific T-cells were mainly CD8+/IFN-γ+ and detectable from d32pi on. Peripheral blood IFN-γ+ T-cell percentages were similar in both infected groups, albeit at low frequency (~0.1%). In summary, the Ab4ΔORF1/71 gene deletion mutant is less virulent but induced antibody responses and cellular immunity similar to the parent Ab4 strain.

Published
2018

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