β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway
Understanding the host response to influenza A virus (IAV) infection is vital for developing intervention strategies. The primary barriers for invading respiratory pathogens are the respiratory tract epithelial cells and antimicrobial proteins generated by these cells. The antimicrobial peptide, β-d...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/12/1/123 |
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| author | Sreekumar Othumpangat John D. Noti |
| author_facet | Sreekumar Othumpangat John D. Noti |
| author_sort | Sreekumar Othumpangat |
| collection | DOAJ |
| description | Understanding the host response to influenza A virus (IAV) infection is vital for developing intervention strategies. The primary barriers for invading respiratory pathogens are the respiratory tract epithelial cells and antimicrobial proteins generated by these cells. The antimicrobial peptide, β-defensin-1, has antiviral activity against both enveloped and non-enveloped viruses. Significant downregulation of β-defensin1 gene (<i>DEFB1</i>) expression was observed when human bronchial epithelial cells (HBEpCs) were exposed to IAV. HBEpCs overexpressing <i>DEFB1</i> caused a significant reduction in IAV, that was confirmed by IAV matrix gene analysis, plaque assay, and confocal microscopy. <i>DEFB1</i> expression after transfection with two micro RNAs (miRNAs), hsa-miR-186-5p and hsa-miR-340-5p, provided evidence that <i>DEFB1</i> expression could be modulated by these miRNAs and hsa-miR-186-5p had a higher binding efficiency with <i>DEFB1</i>. Overexpression of <i>DEFB1</i> in IAV-infected HBEpCs led to increased NF-κB expression. In a PCR array analysis of 84 transcription factors, either overexpressing <i>DEFB1</i> or siRNA silencing of <i>DEFB1</i> expression significantly modulated the expression of signal transducer and activator of transcription 3 (STAT3). In addition, Ingenuity Pathway Analysis (IPA) integrated with PCR array data showed that the JAK1/STAT3 pathway was significantly altered in cells overexpressing <i>DEFB1</i>, suggesting this to be one of the pathways by which defensin regulates IAV replication in HBEpCs. In conclusion, the reduction in IAV copy number in <i>DEFB1</i> overexpressing cells suggests that β-defensin-1 plays a key role in regulating IAV survival through STAT3 and is a potential target for antiviral drug development. |
| first_indexed | 2024-03-09T11:30:00Z |
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| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T11:30:00Z |
| publishDate | 2023-01-01 |
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| series | Pathogens |
| spelling | doaj.art-f8b1e606e53b4f259027eaf46e6b2cbe2023-11-30T23:54:01ZengMDPI AGPathogens2076-08172023-01-0112112310.3390/pathogens12010123β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling PathwaySreekumar Othumpangat0John D. Noti1Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USAAllergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USAUnderstanding the host response to influenza A virus (IAV) infection is vital for developing intervention strategies. The primary barriers for invading respiratory pathogens are the respiratory tract epithelial cells and antimicrobial proteins generated by these cells. The antimicrobial peptide, β-defensin-1, has antiviral activity against both enveloped and non-enveloped viruses. Significant downregulation of β-defensin1 gene (<i>DEFB1</i>) expression was observed when human bronchial epithelial cells (HBEpCs) were exposed to IAV. HBEpCs overexpressing <i>DEFB1</i> caused a significant reduction in IAV, that was confirmed by IAV matrix gene analysis, plaque assay, and confocal microscopy. <i>DEFB1</i> expression after transfection with two micro RNAs (miRNAs), hsa-miR-186-5p and hsa-miR-340-5p, provided evidence that <i>DEFB1</i> expression could be modulated by these miRNAs and hsa-miR-186-5p had a higher binding efficiency with <i>DEFB1</i>. Overexpression of <i>DEFB1</i> in IAV-infected HBEpCs led to increased NF-κB expression. In a PCR array analysis of 84 transcription factors, either overexpressing <i>DEFB1</i> or siRNA silencing of <i>DEFB1</i> expression significantly modulated the expression of signal transducer and activator of transcription 3 (STAT3). In addition, Ingenuity Pathway Analysis (IPA) integrated with PCR array data showed that the JAK1/STAT3 pathway was significantly altered in cells overexpressing <i>DEFB1</i>, suggesting this to be one of the pathways by which defensin regulates IAV replication in HBEpCs. In conclusion, the reduction in IAV copy number in <i>DEFB1</i> overexpressing cells suggests that β-defensin-1 plays a key role in regulating IAV survival through STAT3 and is a potential target for antiviral drug development.https://www.mdpi.com/2076-0817/12/1/123<i>DEFB1</i>bronchial epithelial cellsSTAT pathwayinfluenza virusmiRNA |
| spellingShingle | Sreekumar Othumpangat John D. Noti β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway Pathogens <i>DEFB1</i> bronchial epithelial cells STAT pathway influenza virus miRNA |
| title | β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway |
| title_full | β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway |
| title_fullStr | β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway |
| title_full_unstemmed | β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway |
| title_short | β-Defensin-1 Regulates Influenza Virus Infection in Human Bronchial Epithelial Cells through the STAT3 Signaling Pathway |
| title_sort | β defensin 1 regulates influenza virus infection in human bronchial epithelial cells through the stat3 signaling pathway |
| topic | <i>DEFB1</i> bronchial epithelial cells STAT pathway influenza virus miRNA |
| url | https://www.mdpi.com/2076-0817/12/1/123 |
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