title: Interferon gamma-mediated BoHV-4 replication restriction in bovine endometrial stromal cells is host IDO1 gene expression independent and BoHV-4 IE2 gene expression dependent.
abstract: In the present work the interaction between bovine herpesvirus 4 (BoHV-4)-infected bovine endometrial stromal cells (BESCs) and interferon gamma (IFNG) was investigated. Starting from the particular tropism of BoHV-4 toward BESCs, a pure population of these cells, free of CD45-positive cells, was prepared and proven to have a bona fide mesenchymal derivation as shown by vimentin-positive and cytokeratin-negative staining. BESCs expressed functional IFNG receptors (IFNGR) 1 and 2 but not IFNG ligand. BESCs transfected with a new reporter construct made by cloning the bovine indoleamine 2, 3-dioxygenase 1 (IDO1) promoter in front of the luciferase reporter gene responded to exogenous IFNG treatment. Further, IFNG-treated or constitutively secreting IFNG BESCs strongly restricted BoHV-4 replication and consequent cytopathic effect. IDO1 expression in BESCs was tightly induced by IFNG and IDO1 was previously shown to be the mediator for some of the IFNG pathogenostatic effects. However, IDO1 inhibitors and IDO1 constitutive expression could not respectively abrogate or recapitulate IFNG effect on BoHV-4-infected BESCs, whereas BoHV-4 immediate early (IE2) gene expression was transcriptionally depressed by IFNG axis activation independently from IDO1 expression; this was further confirmed by revealing a BoHV-4 IE2 gene promoter area containing potential responsive elements interacting with inhibitory transcription factors induced by IFNG in BESCs. The data achieved in this work highlight at least two issues: first, the role of BESCs as target/effector cells for the IFNG; second, the importance of uterine IFNG integrity to control BoHV-4 infection recrudescence from a persistent/latent state to a chronic disease, endometritis.
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jacca
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Franceschi
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Agosti
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cavirani
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Mistretta
authors.affiliation: Department of Medical-Veterinary Science, University of Parma, Parma, Italy gaetano.donofrio@unipr.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
mesh_terms: D000818:Animals; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics / Q000821:virology; D002478:Cells, Cultured; D004717:Endometrium / Q000187:drug effects* / Q000821:virology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000235:genetics / Q000662:veterinary / Q000821:virology; D026021:Herpesvirus 4, Bovine / Q000187:drug effects* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000821:virology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014412:Tumor Virus Infections / Q000235:genetics / Q000662:veterinary / Q000821:virology; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: C079185:IE2 protein, bovine herpesvirus type 4; D017874:Immediate-Early Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015534:Trans-Activators; D007371:Interferon-gamma
keywords: IE2 gene; bovine endometrial stromal cells; bovine herpesvirus 4; gamma interferon; postpartum metritis