TY - JOUR
T1 - Estrogenic compounds reduce influenza a virus replication in primary human nasal epithelial cells derived from female, but not male, donors
AU - Peretz, Jackye
AU - Pekosz, Andrew
AU - Lane, Andrew P.
AU - Klein, Sabra L.
N1 - Funding Information:
This work was funded by the Center for Alternatives to Animal Testing Grant 2013-09 (to S. L. Klein) and National Institutes of Health Grants R01-AI-097417 and HHSN272201400007C (to A. Pekosz), R01-AI-72502 (to A. P. Lane), and T32-AI-007417 (to J. Peretz).
Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - Antiviral defenses
KW - Estradiol
KW - Respiratory disease
KW - SERMs
KW - Zinc finger proteins
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U2 - 10.1152/ajplung.00398.2015
DO - 10.1152/ajplung.00398.2015
M3 - Article
C2 - 26684252
AN - SCOPUS:84984614496
SN - 1040-0605
VL - 310
SP - L415-L425
JO - American Journal of Physiology
JF - American Journal of Physiology
IS - 5
ER -