title: Human cytomegalovirus productively infects adrenocortical cells and induces an early cortisol response.
abstract: Following our recent findings on the presence of human cytomegalovirus (HCMV) in the normal human adrenal cortex and in adrenocortical tumors, especially in cortisol-secreting tumors, aim of the present study was to investigate the direct effects of HCMV infection on human adrenocortical cells. To this aim, both clinical isolates and laboratory strains of HCMV were used to assess the early effects of infection on human adrenocortical cell morphology, proliferation, gene expression, and steroidogenic function. Both clinical and laboratory HCMV strains could infect and replicate in primary human adrenocortical cell cultures and in adrenocortical carcinoma cell lines, leading to cytopathic changes. Most importantly, in the first hours post-infection (p.i.), adrenocortical cells showed a significant increase of cortisol and estrogen production, paralleled by up-regulation of steroidogenic acute regulatory protein and expression of steroidogenic enzymes involved in the last steps of adrenal steroidogenesis. This effect was probably due to HCMV immediate-early gene expression, since it was most evident in the early phases p.i. and UV-inactivated viral particles did not affect hormone production. Moreover, the effect on steroidogenesis was HCMV specific, since it was not observed after infection with herpes simplex virus. These data suggest that human adrenocortical cells are permissive to HCMV infection and acutely respond to infection with increased cortisol production. An acute glucocorticoid response is typically triggered by infections and is considered to be critical to host defense against pathogens, although, in the case of HCMV infection, it might also enhance viral replication and reactivation from latency.
authors.affiliation: Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Padova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Trevisan
authors.forename: Urska
authors.initials: U
authors.lastname: Matkovic
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cusinato
authors.forename: Stefano
authors.initials: S
authors.lastname: Toppo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D000616:Aminoglutethimide / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D003587:Cytomegalovirus / Q000254:growth & development*; D003588:Cytopathogenic Effect, Viral; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004958:Estradiol / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D018259:Herpesvirus 1, Human / Q000254:growth & development; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D014759:Viral Envelope Proteins / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D014759:Viral Envelope Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C065418:cytomegalovirus matrix protein 65kDa; C040495:glycoprotein B, Simplexvirus; D000098682:Steroidogenic Acute Regulatory Protein; D000616:Aminoglutethimide; D004958:Estradiol; D006854:Hydrocortisone