title: Bovine herpesvirus 4 is tropic for bovine endometrial cells and modulates endocrine function.
abstract: Bovine postpartum uterine disease, metritis, affects about 40% of animals and is widely considered to have a bacterial aetiology. Although the gamma-herpesvirus bovine herpesvirus 4 (BoHV-4) has been isolated from several outbreaks of metritis or abortion, the role of viruses in endometrial pathology and the mechanisms of viral infection of uterine cells are often ignored. The objectives of the present study were to explore the interaction, tropism and outcomes of BoHV-4 challenge of endometrial stromal and epithelial cells. Endometrial stromal and epithelial cells were purified and infected with a recombinant BoHV-4 carrying an enhanced green fluorescent protein (EGFP) expression cassette to monitor the establishment of infection. BoHV-4 efficiently infected both stromal and epithelial cells, causing a strong non-apoptotic cytopathic effect, associated with robust viral replication. The crucial step for the BoHV-4 endometriotropism appeared to be after viral entry as there was enhanced transactivation of the BoHV-4 immediate early 2 gene promoter following transient transfection into the endometrial cells. Infection with BoHV-4 increased cyclooxygenase 2 protein expression and prostaglandin estradiol secretion in endometrial stromal cells, but not epithelial cells. Bovine macrophages are persistently infected with BoHV-4, and co-culture with endometrial stromal cells reactivated BoHV-4 replication in the persistently infected macrophages, suggesting a symbiotic relationship between the cells and virus. In conclusion, the present study provides evidence of cellular and molecular mechanisms, supporting the concept that BoHV-4 is a pathogen associated with uterine disease.
authors.affiliation: Dipartimento di Salute Animale, Sezione di Malattie Infettive, Facoltà di Medicina Veterinaria, via del Taglio 8, 43100 Parma, Italy. gaetano.donofrio@unipr.it
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
authors.forename: Shan
authors.initials: S
authors.lastname: Herath
authors.forename: Chiara
authors.initials: C
authors.lastname: Sartori
authors.forename: Sandro
authors.initials: S
authors.lastname: Cavirani
authors.forename: Cesidio Filippo
authors.initials: CF
authors.lastname: Flammini
authors.forename: Iain Martin
authors.initials: IM
authors.lastname: Sheldon
mesh_terms: D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002418:Cattle Diseases / Q000821:virology*; D016923:Cell Death; D002460:Cell Line; D004716:Endometritis / Q000662:veterinary / Q000821:virology*; D004717:Endometrium / Q000378:metabolism / Q000821:virology*; D005260:Female; D005814:Genes, Viral; D049452:Green Fluorescent Proteins / Q000235:genetics; D006566:Herpesviridae Infections / Q000662:veterinary / Q000821:virology*; D026021:Herpesvirus 4, Bovine / Q000235:genetics / Q000472:pathogenicity*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000821:virology; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D008969:Molecular Sequence Data; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011458:Prostaglandins E / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism / Q000821:virology; D015534:Trans-Activators; D014779:Virus Replication
chemical_list: D008070:Lipopolysaccharides; D011458:Prostaglandins E; D015534:Trans-Activators; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins