tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2025 Dec;14(1):2532684.
doi: 10.1080/22221751.2025.2532684. Epub 2025 Jul 25. Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids
Hussin Rothan[SUP] 1 2 [/SUP], Ahmed Mostafa[SUP] 1 2 [/SUP], Mahmoud Bayoumi[SUP] 1 [/SUP], Chengjin Ye[SUP] 1 2 [/SUP], Ramya S Barre[SUP] 1 [/SUP], Anna Allué-Guardia[SUP] 2 3 [/SUP], Aitor Nogales[SUP] 4 [/SUP], Jordi B Torrelles[SUP] 2 3 [/SUP], Luis Martinez-Sobrido[SUP] 1 2 [/SUP]
Affiliations
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.
Keywords: Human airway organoids; ROCK signalling pathway; fibrogenesis; influenza virus; prolonged infection.
. 2025 Dec;14(1):2532684.
doi: 10.1080/22221751.2025.2532684. Epub 2025 Jul 25. Emerging highly pathogenic H5N1 influenza triggers fibrotic remodeling in human airway organoids
Hussin Rothan[SUP] 1 2 [/SUP], Ahmed Mostafa[SUP] 1 2 [/SUP], Mahmoud Bayoumi[SUP] 1 [/SUP], Chengjin Ye[SUP] 1 2 [/SUP], Ramya S Barre[SUP] 1 [/SUP], Anna Allué-Guardia[SUP] 2 3 [/SUP], Aitor Nogales[SUP] 4 [/SUP], Jordi B Torrelles[SUP] 2 3 [/SUP], Luis Martinez-Sobrido[SUP] 1 2 [/SUP]
Affiliations
- PMID: 40712003
- DOI: 10.1080/22221751.2025.2532684
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.
Keywords: Human airway organoids; ROCK signalling pathway; fibrogenesis; influenza virus; prolonged infection.