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MIWI2 Regulates Mitochondrial Gene Expression During Influenza and Exacerbates Disease Outcome

ABSTRACT: The airway epithelium, consisting of diverse cell types, plays a vital role in defending against respiratory viruses. MIWI2 multiciliated (M2MC) cells are a rare subpopulation of multiciliated cells distinguished by the expression of MIWI2, the mouse analogous PIWIL4 argonaute family protein. While recognized for its role in repressing retrotransposons during spermatogenesis and regulating viral RNA in mosquitos, the function of MIWI2 in M2MC cells remains poorly understood. This study explores the transcriptomic changes in retrotransposons, viral RNAs, and host genes in an effort to elucidate MIWI2’s role in the airway. M2MC and nonM2MC cells were sorted from digested lungs of MIWI2 haplosufficient (Miwi2+/tom) and deficient (Miwi2tom/tom) mice intratracheally instilled with saline or mouse adapted A/Puerto Rico/8/1934 (PR8) IAV three days post infection. Our findings indicated that retrotransposon and viral RNA expression is independent of MIWI2 expression. However, MIWI2 deficiency decreased mitochondrial and ribosomal gene expression in M2MC cells during PR8 infection. In addition, a decrease in small RNAs mapped to nuclear mitochondrial (NuMT) DNA was observed in saline treated MIWI2 expressing cells. These findings were then followed up by flow cytometry studies where an increase in intracellular reactive oxygen species (ROS) was observed in PR8 infected multiciliated cells from Miwi2tom/tom mice. In addition, Miwi2tom/tom mice experience decreased viral titer and RNA 7 days post infection and recovered faster in percent body weight compared to wild-type and Miwi2+/tom mice. These studies suggest that MIWI2 exacerbates IAV outcomes by regulating mitochondrial gene expression and function. These results reveal a novel role for MIWI2 in somatic cells and propose MIWI2/PIWIL4 as a potential biomarker for susceptibility to severe respiratory infections. Understanding MIWI2-dependent pathways could lead to new therapeutic targets for respiratory viral infections.

ORGANISM(S): Mus musculus

PROVIDER: GSE276578 | GEO | 2025/02/25

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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MIWI2 Regulates Mitochondrial Gene Expression During Influenza and Exacerbates Disease Outcome

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