Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids
The ongoing outbreak of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b has affected at least 989 dairy herds across 17 states in the United States (U.S.) and resulted in 70 confirmed human infections, underscoring the urgent need to understand the pathogenesis and therapeutic intervent...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2025.2532684 |
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| author | Hussin Rothan Ahmed Mostafa Mahmoud Bayoumi Chengjin Ye Ramya S. Barre Anna Allué-Guardia Aitor Nogales Jordi B. Torrelles Luis Martinez-Sobrido |
| author_facet | Hussin Rothan Ahmed Mostafa Mahmoud Bayoumi Chengjin Ye Ramya S. Barre Anna Allué-Guardia Aitor Nogales Jordi B. Torrelles Luis Martinez-Sobrido |
| author_sort | Hussin Rothan |
| collection | DOAJ |
| description | The ongoing outbreak of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b has affected at least 989 dairy herds across 17 states in the United States (U.S.) and resulted in 70 confirmed human infections, underscoring the urgent need to understand the pathogenesis and therapeutic interventions of emerging H5N1 viruses. In this study, we modelled infection with a highly pathogenic recombinant human A/Texas/37/2024 H5N1 (rHPh-TX H5N1) strain using human airway organoids (HAO) to investigate viral replication, innate immune response, infection-induced fibrogenesis, and potential therapeutic interventions. rHPh-TX H5N1 replicated efficiently in HAO, eliciting a robust interferon (IFN) response and pro-inflammatory cytokine production. Prolonged infection led to the accumulation of fibroblast-like cells surrounding infected regions, marked by increased alpha-smooth muscle actin (α-SMA) expression and upregulation of transforming growth factor-beta (TGF-β), indicative of fibroblast activation and extracellular matrix (ECM) remodelling. Compared to organoids infected with the pandemic A/California/04/09 H1N1 (pH1N1) strain, rHPh-TX H5N1 induced significantly higher expression of fibrosis-associated markers, including fibronectin (FN), collagen 1A (COL1A), collagen 3A (COL3A), metalloproteinases 2 and 9 (MMP2, and MMP9). Notably, the inhibition of Rho-associated coiled-coil-forming protein kinases (ROCK) signalling reduced fibrogenesis, with ROCK1 inhibition being more effective than ROCK2 inhibition. These findings highlight the potential of targeting ROCK signalling to mitigate H5N1-induced lung fibrosis, informing therapeutic strategies for severe influenza infections. |
| format | Article |
| id | doaj-art-6f55a3cf34bc409c850490a48e36c924 |
| institution | Kabale University |
| issn | 2222-1751 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj-art-6f55a3cf34bc409c850490a48e36c9242025-08-20T03:56:47ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512025-12-0114110.1080/22221751.2025.2532684Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoidsHussin Rothan0Ahmed Mostafa1Mahmoud Bayoumi2Chengjin Ye3Ramya S. Barre4Anna Allué-Guardia5Aitor Nogales6Jordi B. Torrelles7Luis Martinez-Sobrido8Host-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAHost-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAHost-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAHost-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAHost-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAInternational Center for the Advancement of Research and Education (I•CARE), Texas Biomedical Research Institute, San Antonio, TX, USACenter for Animal Health Research, CISA-INIA-CSIC, Madrid, SpainInternational Center for the Advancement of Research and Education (I•CARE), Texas Biomedical Research Institute, San Antonio, TX, USAHost-pathogen interactions (HPI) and Disease Intervention and Prevention (DIP) Programs, Texas Biomedical Research Institute, San Antonio, TX, USAThe ongoing outbreak of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b has affected at least 989 dairy herds across 17 states in the United States (U.S.) and resulted in 70 confirmed human infections, underscoring the urgent need to understand the pathogenesis and therapeutic interventions of emerging H5N1 viruses. In this study, we modelled infection with a highly pathogenic recombinant human A/Texas/37/2024 H5N1 (rHPh-TX H5N1) strain using human airway organoids (HAO) to investigate viral replication, innate immune response, infection-induced fibrogenesis, and potential therapeutic interventions. rHPh-TX H5N1 replicated efficiently in HAO, eliciting a robust interferon (IFN) response and pro-inflammatory cytokine production. Prolonged infection led to the accumulation of fibroblast-like cells surrounding infected regions, marked by increased alpha-smooth muscle actin (α-SMA) expression and upregulation of transforming growth factor-beta (TGF-β), indicative of fibroblast activation and extracellular matrix (ECM) remodelling. Compared to organoids infected with the pandemic A/California/04/09 H1N1 (pH1N1) strain, rHPh-TX H5N1 induced significantly higher expression of fibrosis-associated markers, including fibronectin (FN), collagen 1A (COL1A), collagen 3A (COL3A), metalloproteinases 2 and 9 (MMP2, and MMP9). Notably, the inhibition of Rho-associated coiled-coil-forming protein kinases (ROCK) signalling reduced fibrogenesis, with ROCK1 inhibition being more effective than ROCK2 inhibition. These findings highlight the potential of targeting ROCK signalling to mitigate H5N1-induced lung fibrosis, informing therapeutic strategies for severe influenza infections.https://www.tandfonline.com/doi/10.1080/22221751.2025.2532684Human airway organoidsinfluenza virusprolonged infectionfibrogenesisROCK signalling pathway |
| spellingShingle | Hussin Rothan Ahmed Mostafa Mahmoud Bayoumi Chengjin Ye Ramya S. Barre Anna Allué-Guardia Aitor Nogales Jordi B. Torrelles Luis Martinez-Sobrido Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids Emerging Microbes and Infections Human airway organoids influenza virus prolonged infection fibrogenesis ROCK signalling pathway |
| title | Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids |
| title_full | Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids |
| title_fullStr | Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids |
| title_full_unstemmed | Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids |
| title_short | Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids |
| title_sort | emerging highly pathogenic h5n1 influenza triggers fibrotic remodeling in human airway organoids |
| topic | Human airway organoids influenza virus prolonged infection fibrogenesis ROCK signalling pathway |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2025.2532684 |
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