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.

The M2 protein of live, attenuated influenza vaccine encodes a mutation that reduces replication in human nasal epithelial cells

“…Primary, differentiated epithelial cell cultures have been shown to provide greater clinical relevance and phenotype penetrance than immortalized cell lines [10,11,18,39–44]. This is particularly true for studying LAIV [10,11].…”

Potential interventions for novel coronavirus in China: A systematic review

“…Interestingly, estrogenic compounds had been found to reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. 128 In addition, resveratrol, a phytoestrogen from grape seeds and red wine, had been reported to be a potent anti-MERS agent in vitro. 129 Therefore, 17β-Estradiol or phytoestrogen could also be an alternative option to be considered for the treatment of COVID-19.…”

Sex Drives Dimorphic Immune Responses to Viral Infections

“…With regard to gene dosage on sex chromosomes, X-linked genes such as IL-13, IL-4, IL-10, Xist, Tlr7, FoxP3 on X chromosome and Sry (testis-determining factor), Sox9 (SRY-box 9) on Y chromosome may underlie sexually dimorphic responses that contribute to stronger innate, cellular and humoral immune responses and susceptibility to autoimmune diseases in females compared with males (13–15). Studies in humans and animal models indicate sexually dimorphic mechanisms that contribute to virologic control during infections with human immunodeficiency virus (HIV)-1, vesicular stomatitis virus (VSV), hantavirus (Seoul virus), influenza virus (H1N1), hepatitis C virus, Theiler’s murine encephalomyelitis virus (TMEV), herpes simplex virus (HSV-1) and coxsackievirus B3 (CVB3) (5, 16–20). In this review, we will introduce the various mechanisms that impose sexual dimorphism in immune function in males and females.…”