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Rhinovirus triggers distinct host responses through differential engagement of epithelial innate immune signaling [RNA-Seq]

ABSTRACT: Rhinovirus (RV) is the most frequent cause of common colds, but also a major cause of serious respiratory illness in high-risk groups (e.g. smokers and asthmatics). The molecular mechanisms leading to disparate outcomes of infection are not fully understood. Variation in the host epithelial interferon response has been implicated susceptibly to RV illness. We performed single cell sequencing air-liquid interface (ALI) cultured human nasal epithelial cells (HNECs) with infection of HRV-01A in the presence of IRF3 activation inhibitor BX795. We showed that the epithelial interferon response restricts RV infection to <2% of cells, however, inhibiting IRF3 activation increases the proportion of infected cells to >30%, and leads to a distinct NFKB-dependent pro-inflammatory response, with production of neutrophil-attracting chemokines, increased mucus, and IL-1b. Bulk RNA sequencing further revealed that inhibiting both IRF3 and NFKB induce ER stress and squamous metaplasia genes. Overall, our study demonstrates how distinct forms of epithelial defense responses impact RV-induced inflammation.

ORGANISM(S): Human rhinovirus 1A Homo sapiens

PROVIDER: GSE286616 | GEO | 2026/03/10

REPOSITORIES: GEO

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Project description:E2 exposure significantly decreased peak viral titer in hNECs from female donors. We used microarray analyses to identify global gene expression patterns between E2 and vehicle exposed hNECs from female donors 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 17Î²-estradiol (E2) or select estrogen receptor modulators (SERMs), 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 where 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 non- genomic GPR30 were 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. Primary human nasal epithelial cells from females were exposed to E2 for 24h prior to infection, then infected with an H3N2 strain of influenza a virus for 2 hours. At 24 and 48h post infection, hNECs were collected in Trizol for RNA extraction and hybridization on Affymetrix Human Gene ST 2.0 microarrays.

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Rhinovirus triggers distinct host responses through differential engagement of epithelial innate immune signaling [RNA-Seq]

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