Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome
BackgroundChildren with Down Syndrome (DS) are at high risk for severe respiratory syncytial virus (RSV) infections. DS is associated with impaired cellular responses to oxidative stress and hypoxia; however, these abnormalities have not been explored in trisomy 21 (TS21) airway epithelial cells (AE...
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Frontiers Media S.A.
2025-05-01
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| author | Allison Welham Allison Welham Allison Welham Elizabeth Chorvinsky Elizabeth Chorvinsky Elizabeth Chorvinsky Surajit Bhattacharya Surajit Bhattacharya Surajit Bhattacharya Kyle Salka Betelehem Solomon Bera Betelehem Solomon Bera Betelehem Solomon Bera Woudasie Admasu Woudasie Admasu Woudasie Admasu Maria C. Straker Maria C. Straker Maria C. Straker Maria J. Gutierrez Jyoti K. Jaiswal Jyoti K. Jaiswal Gustavo Nino Gustavo Nino Gustavo Nino |
| author_facet | Allison Welham Allison Welham Allison Welham Elizabeth Chorvinsky Elizabeth Chorvinsky Elizabeth Chorvinsky Surajit Bhattacharya Surajit Bhattacharya Surajit Bhattacharya Kyle Salka Betelehem Solomon Bera Betelehem Solomon Bera Betelehem Solomon Bera Woudasie Admasu Woudasie Admasu Woudasie Admasu Maria C. Straker Maria C. Straker Maria C. Straker Maria J. Gutierrez Jyoti K. Jaiswal Jyoti K. Jaiswal Gustavo Nino Gustavo Nino Gustavo Nino |
| author_sort | Allison Welham |
| collection | DOAJ |
| description | BackgroundChildren with Down Syndrome (DS) are at high risk for severe respiratory syncytial virus (RSV) infections. DS is associated with impaired cellular responses to oxidative stress and hypoxia; however, these abnormalities have not been explored in trisomy 21 (TS21) airway epithelial cells (AECs) during RSV infection. Understanding these defects is key to identifying factors contributing to severe RSV infections in this high-risk group.MethodsAECs from children with and without DS were analyzed at baseline and after RSV infection to assess NRF2-induced protective genes against oxidative stress and hypoxia, including the enzyme heme oxygenase 1 (HO-1). To investigate DS-specific defects, we focused on miR-155 and BACH1, which regulate NRF2 signaling and HO-1 expression, and are both encoded on chromosome 21. RNA-seq analyses were performed to examine genome-wide hypoxia-related gene responses in control and TS21 AECs at baseline and after RSV infection.ResultsOur findings show that miR-155 inhibits BACH1, leading to increased NRF2-driven HO-1 expression in euploid AECs. In contrast, TS21 AECs from children with DS exhibited impaired HO-1 induction following miR-155 treatment. This was attributed to reduced transcription of the HMOX1 gene, which encodes HO-1, along with global downregulation of hypoxia response genes in DS at baseline and after RSV infection in TS21 AECs.ConclusionsSevere RSV infections in children with DS may be linked to intrinsic defects in AEC responses to hypoxia, including NRF2-driven cytoprotective enzymes like HO-1. These findings offer new mechanistic insights into RSV pathophysiology and potential therapeutic targets in children with DS. |
| format | Article |
| id | doaj-art-acdc62110f564ea9ac4e22d59fdebec8 |
| institution | OA Journals |
| issn | 2296-2360 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj-art-acdc62110f564ea9ac4e22d59fdebec82025-08-20T01:55:22ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602025-05-011310.3389/fped.2025.15535711553571Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndromeAllison Welham0Allison Welham1Allison Welham2Elizabeth Chorvinsky3Elizabeth Chorvinsky4Elizabeth Chorvinsky5Surajit Bhattacharya6Surajit Bhattacharya7Surajit Bhattacharya8Kyle Salka9Betelehem Solomon Bera10Betelehem Solomon Bera11Betelehem Solomon Bera12Woudasie Admasu13Woudasie Admasu14Woudasie Admasu15Maria C. Straker16Maria C. Straker17Maria C. Straker18Maria J. Gutierrez19Jyoti K. Jaiswal20Jyoti K. Jaiswal21Gustavo Nino22Gustavo Nino23Gustavo Nino24Division of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesJacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University, Baltimore, MD, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesDivision of Pediatric Pulmonary and Sleep Medicine, Children’s National Hospital, Washington, DC, United StatesCenter for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United StatesDepartment of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC, United StatesBackgroundChildren with Down Syndrome (DS) are at high risk for severe respiratory syncytial virus (RSV) infections. DS is associated with impaired cellular responses to oxidative stress and hypoxia; however, these abnormalities have not been explored in trisomy 21 (TS21) airway epithelial cells (AECs) during RSV infection. Understanding these defects is key to identifying factors contributing to severe RSV infections in this high-risk group.MethodsAECs from children with and without DS were analyzed at baseline and after RSV infection to assess NRF2-induced protective genes against oxidative stress and hypoxia, including the enzyme heme oxygenase 1 (HO-1). To investigate DS-specific defects, we focused on miR-155 and BACH1, which regulate NRF2 signaling and HO-1 expression, and are both encoded on chromosome 21. RNA-seq analyses were performed to examine genome-wide hypoxia-related gene responses in control and TS21 AECs at baseline and after RSV infection.ResultsOur findings show that miR-155 inhibits BACH1, leading to increased NRF2-driven HO-1 expression in euploid AECs. In contrast, TS21 AECs from children with DS exhibited impaired HO-1 induction following miR-155 treatment. This was attributed to reduced transcription of the HMOX1 gene, which encodes HO-1, along with global downregulation of hypoxia response genes in DS at baseline and after RSV infection in TS21 AECs.ConclusionsSevere RSV infections in children with DS may be linked to intrinsic defects in AEC responses to hypoxia, including NRF2-driven cytoprotective enzymes like HO-1. These findings offer new mechanistic insights into RSV pathophysiology and potential therapeutic targets in children with DS.https://www.frontiersin.org/articles/10.3389/fped.2025.1553571/fulltrisomy 21 (Down syndrome)RSV (respiratory syncytial virus)airway epitheliamiR-155hypoxia |
| spellingShingle | Allison Welham Allison Welham Allison Welham Elizabeth Chorvinsky Elizabeth Chorvinsky Elizabeth Chorvinsky Surajit Bhattacharya Surajit Bhattacharya Surajit Bhattacharya Kyle Salka Betelehem Solomon Bera Betelehem Solomon Bera Betelehem Solomon Bera Woudasie Admasu Woudasie Admasu Woudasie Admasu Maria C. Straker Maria C. Straker Maria C. Straker Maria J. Gutierrez Jyoti K. Jaiswal Jyoti K. Jaiswal Gustavo Nino Gustavo Nino Gustavo Nino Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome Frontiers in Pediatrics trisomy 21 (Down syndrome) RSV (respiratory syncytial virus) airway epithelia miR-155 hypoxia |
| title | Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome |
| title_full | Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome |
| title_fullStr | Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome |
| title_full_unstemmed | Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome |
| title_short | Impaired airway epithelial miR-155/BACH1/NRF2 axis and hypoxia gene expression during RSV infection in children with down syndrome |
| title_sort | impaired airway epithelial mir 155 bach1 nrf2 axis and hypoxia gene expression during rsv infection in children with down syndrome |
| topic | trisomy 21 (Down syndrome) RSV (respiratory syncytial virus) airway epithelia miR-155 hypoxia |
| url | https://www.frontiersin.org/articles/10.3389/fped.2025.1553571/full |
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