title: Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors.
abstract: Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17β-estradiol (E2) or select estrogen receptor modulators (SERMs) and then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects were sex dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor-2 (ESR2) as neither genomic ESR1 nor nongenomic GPR30 was expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: Jackye
authors.initials: J
authors.lastname: Peretz
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: Andrew
authors.initials: A
authors.lastname: Pekosz
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lane
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and sklein2@jhu.edu.
authors.forename: Sabra L
authors.initials: SL
authors.lastname: Klein
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy; D008297:Male; D051379:Mice; D011247:Pregnancy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D004967:Estrogens; D020849:Raloxifene Hydrochloride
keywords: SERMs; antiviral defenses; estradiol; respiratory disease; zinc finger proteins