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The virus causes respiratory disease, abortion, and, in some cases, neurological disease. EHV-1 strain KyA is attenuated in the mouse and equine, whereas wild-type strain RacL11 induces severe inflammation of the lung, causing infected mice to succumb at 4 to 6 days postinfection. Our previous results showed that KyA immunization protected CBA mice from pathogenic RacL11 challenge at 2 and 4 weeks postimmunization and that KyA infection elicited protective humoral and cell-mediated immune responses. To investigate the protective mechanisms of innate immune responses to KyA, KyA-immunized mice were challenged with RacL11 at various times postvaccination. KyA immunization protected mice from RacL11 challenge at 1 to 7 days postimmunization. Immunized mice lost less than 10% of their body weight and rapidly regained weight. Virus titers in the lungs of KyA-immunized mice were 1,000-fold lower at 2 days post-RacL11 challenge than virus titers in the lungs of nonimmunized mice, indicating accelerated virus clearance. Affymetrix microarray analysis revealed that gamma interferon (IFN-\u03b3) and 16 antiviral interferon-stimulated genes (ISGs) were upregulated 3.1- to 48.2-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been immunized with KyA. Murine IFN-\u03b3 inhibited EHV-1 infection of murine alveolar macrophages and protected mice against lethal EHV-1 challenge, suggesting that IFN-\u03b3 expression is important in mediating the protection elicited by KyA immunization. These results suggest that EHV-1 KyA may be used as a live attenuated EHV-1 vaccine as well as a prophylactic agent in horses.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Viral infection of cells initiates a signal cascade of events that ultimately attempts to limit viral replication and prevent infection through the expression of host antiviral proteins. In this study, we show that EHV-1 KyA immunization effectively protected CBA mice from pathogenic RacL11 challenge at 1 to 7 days postvaccination and increased the expression of IFN-\u03b3 and 16 antiviral interferon-stimulated genes (ISGs). The administration of IFN-\u03b3 blocked EHV-1 replication in murine alveolar macrophages and mouse lungs and protected mice from lethal challenge. To our knowledge, this is the first report of an attenuated EHV-1 vaccine that protects the animal at 1 to 7 days postimmunization by innate immune responses. Our findings suggested that IFN-\u03b3 serves as a novel prophylactic agent and may offer new strategies for the development of anti-EHV-1 agents in the equine.<\/jats:p>","DOI":"10.1128\/jvi.00986-16","type":"journal-article","created":{"date-parts":[[2016,6,30]],"date-time":"2016-06-30T02:59:15Z","timestamp":1467255555000},"page":"8090-8104","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Immunization with Attenuated Equine Herpesvirus 1 Strain KyA Induces Innate Immune Responses That Protect Mice from Lethal Challenge"],"prefix":"10.1128","volume":"90","author":[{"given":"Seong K.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhalesh K.","family":"Shakya","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"O'Callaghan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"78","article-title":"Molecular epizootiology, pathogenesis, and prophylaxis of equine herpesvirus-1 infections","volume":"2","author":"Allen GP","year":"1986","unstructured":"Allen GP, Bryans JT. 1986. 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