#Cattle and #human #organoids reveal 2.3.4.4b #H5N1 cross-species #transmission potential and #neuraminidase-specific neutralizing #antibodies in humans

 

Abstract

The unexpected circulation of clade 2.3.4.4b H5N1 influenza viruses in dairy cattle and the transmission to diverse mammalian species poses a pandemic risk. We sought to explore cattle and human respiratory susceptibility to the 2.3.4.4b H5N1 virus. We establish long-term expandable cattle airway and mammary organoids. The 2.3.4.4b H5N1 virus exhibits high replicative fitness in cattle mammary organoids, recapitulating its remarkable mammary tropism. The virus also replicates robustly in cattle airway organoids, suggesting an underrecognized respiratory component in ongoing outbreaks. Interestingly, human airway and nasal organoids are highly susceptible to the 2.3.4.4b H5N1 virus. Yet, a novel organoid-based neutralization assay reveals that N1 antibodies in human sera had cross-neutralizing activity against the 2.3.4.4b H5N1 and ancestral H5N1-VN1194 viruses. The cross-neutralization, exclusively manifested in the organoid-based assay, is enhanced after seasonal influenza vaccination and diminished after depleting N1-specific antibodies. Therefore, cross-neutralizing N1 antibodies are likely limiting zoonotic infection by H5N1 viruses in humans.

Source: 

Link: https://www.nature.com/articles/s41467-026-74345-w

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#Airway #organoids reveal #patterns of #Influenza A tropism and #adaptation in #wildlife species

 

Abstract

Identifying animal species that are susceptible to the plethora of existing and emerging viruses is critical for predicting and containing disease outbreaks. Current efforts to assess viral tropism largely rely on experimental infection models, but such experiments are logistically and ethically infeasible for many wildlife species. To tackle this challenge, we developed a panel of airway organoids from ten taxonomically diverse wildlife and livestock species and evaluated their susceptibility to influenza viruses of mammalian (pH1N1) and avian (H5N1) origin. Our analyses revealed large species-specific differences in infection rate and cytopathogenicity that aligned with known in vivo data and field observations. Furthermore, we demonstrated that this organoid panel can serve as a powerful tool to elucidate receptor-binding mechanisms, viral dynamics, and early host adaptation in poorly characterized animal species. In summary, this work provides a robust and ethically viable approach for evaluating viral tropism and adaptation in wildlife species, and fills a critical gap in current pandemic preparedness, zoonotic disease surveillance, and wildlife conservation efforts.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

Ministerio de Ciencia, Innovación y Universidades, https://ror.org/05r0vyz12, PLEC2022-009171, RYC2021-033035-I, PID2023-147498OB-I00, JDC2023050389-I

European Commission, HORIZON-HLTH-2021 CORONA-01, HORIZON-HLTH-2023-DISEASE-03

CERCA Institution, https://ror.org/01bkbaq61

Source: 

Link: https://www.biorxiv.org/content/10.64898/2025.12.17.694819v1

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#MERS-CoV and #SARS-CoV-2 #infection in diverse #human lung #organoid-derived cultures

 

ABSTRACT

Cell cultures are widely used to study infectious respiratory diseases and to test therapeutics; however, they do not faithfully recapitulate the architecture and complexity of the human respiratory tract. Lung organoids have emerged as an alternative model that partially overcomes this key disadvantage. Lung organoids can be cultured in various formats that offer potential for studying highly pathogenic viruses. However, the effects of these different formats on virus infection remain unexplored, leaving their relative value unclear. In this study, we generated primary lung organoids from human donor cells and used them to derive monolayers and air-liquid interface (ALI) cultures with the goal of comparing the replication kinetics of two circulating highly pathogenic coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV). Infection studies revealed that organoid-derived monolayers displayed limited infection, and the innate immune response was impaired against bacterial lipopolysaccharide (LPS) but not against virus-like double-stranded RNA (dsRNA) or poly(I:C). Meanwhile, organoids and organoid-derived ALI cultures retained viral permissivity, with ALI cultures displaying diverse antiviral immune responses against both coronaviruses. SARS-CoV-2 and MERS-CoV demonstrated differential replication kinetics in organoid and organoid-derived ALI cultures. Therefore, primary organoid-derived cells in two-dimensional monolayer or three-dimensional ALI formats influence virus infection and host antiviral responses. Our study informs the selection of culture conditions for organoid-based respiratory disease research and therapeutic testing.

IMPORTANCE

The COVID-19 pandemic heralded the upsurge in human-derived lung organoid-based studies due to their cellular heterogeneity that partly emulates the cellular complexity of the respiratory tract. A major disadvantage of organoid models resides in their apical-in conformation that “hides” cells and proteins that are typically exposed to the air-liquid interface (ALI) in the airways and are targets of viruses. Here, we generated monolayers and ALI cultures to facilitate cell exposure to highly relevant pathogens and compared them to parental organoids. Organoids at the ALI captured infection and immune responses better than organoids and organoid-derived monolayer cultures. Organoids at the ALI are a viable approach to improve identification and characterization of virus infection, host responses, and therapeutic testing.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.01098-25?af=R

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