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The urgent need for COVID-19 countermeasures during the pandemic highlighted the importance of accurate tissue culture models. Organoids, mini organ replicas grown in vitro from specific cells, faithfully mimic the architecture, functionality and cellular composition of human organs, providing more reliable models than animals or traditional cell lines in the study of virus behaviour.  

Since the nose is the main entry point for SARS-CoV-2, researchers developed organoid models replicating human nasal tissues to investigate how both the ancestral strain of SARS-CoV-2 and the Alpha variant, the first variant of concern, interact with various types of nasal cells across different age groups. 

The study, published in iScience, examined gene activity in individual cells of adult and child nasal organoid models infected with SARS-CoV-2. Researchers observed that COVID-19 affects gene expression differently based on age, virus strain and the cell-types within nasal tissue. 

University of Melbourne’s Professor Lachlan Coin, Laboratory Head and co-Lead of the Computational Sciences and Genomics cross-cutting discipline at the Doherty Institute and co-senior author of the paper said that the findings emphasised the pivotal role of organoids in studying the innate immune response to viral infection.  

“We found that the original strain of SARS-CoV-2 infects children aged 12-14 more effectively than adults aged 26-32, while the Alpha variant infects both age groups at similarly high levels,” said Professor Coin.  

The research also showed that nasal tissue cells mount a more robust innate immune response against the Alpha variant than against the ancestral strain, especially protein processing in children, highlighting age-specific effects of the virus on nasal tissue cells.  

“Out of the 19 different cell-types identified within the organoids, cells with numerous hair-like structures, called cilia, and hybrid ciliated cells that produce secretions into the nasal cavity were the most affected by the virus,” added Professor Coin. 

University of Melbourne’s Professor Elizabeth Vincan, Clinical Scientist and Researcher at the Victorian Infectious Diseases Reference Laboratory (VIDRL) at the Doherty Institute and co-senior author of the paper, highlighted a significant discovery about SARS-CoV-2 replication. 

“One of the most intriguing findings was how SARS-CoV-2 may rely on oxidative phosphorylation, a process essential for recharging the cells’ energy molecules,” said Professor Vincan. 

“ATP, a molecule that carries energy within a cell, is like the cell's rechargeable batteries. Without charged ATP, SARS-CoV-2 can't replicate.” 

“We also observed that uninfected bystander cells initially may attempt to slow down this energy production process, only for the levels to revert to normal once the cells become infected, thereby facilitating viral replication.” 

Professor Coin said human organoids are clearly a game changer and offer a realistic and versatile platform for biomedical research.  

“Over the past 15 years, more than 90 per cent of novel antiviral therapies that showed promise in cell line and animal pre-clinical models failed human clinical trials due to efficacy and toxicity concerns. Human organoids fill this gap and the technological advances in single-cell transcriptomics enable us to interrogate host-pathogen interactions in unprecedented detail,” said Professor Coin.  

“By replicating the primary site of SARS-CoV-2 infection, these organoid models offer a promising platform for testing preventive and therapeutic strategies, with the potential to significantly impact public health.” 

Further research is key to exploring these dynamics across different age groups and newer virus strains. 

• Peer review:  Chang J, et al. Uncovering strain- and age-dependent innate immune responses to SARS-CoV-2 infection in air-liquid-interface cultured nasal epithelia. iScience (2024). https://doi.org/10.1016/j.isci.2024.110009 

• Collaboration:  This research is a result of collaboration between researchers at the Doherty Institute, with complementary expertise in organoids, genomics and virology.  

• Funding:  Kim Wright Foundation, National Health and Medical Research Council (NHMRC), UNSW Scientia program, Miller Foundation and the Australian Government Research Training Program (RTP).