02 Feb 2022
Lab grown, human nasal tissue provides ideal model for SARS-CoV-2 infection leading to more accurate modelling of human disease
Peer review: International Journal of Molecular Sciences
Funding: Kim Wright Foundation
Researchers at the Doherty Institute have been able to show that lab grown, human nasal tissue known as organoids, is a robust model to test the effects of SARS-CoV-2 infection, enabling more accurate testing of COVID-19 treatments.
Since the beginning of the pandemic, there has been a global push to discover medical countermeasures to combat COVID-19.
However traditional methods of testing infection and treatments in conventional cell lines were proving inaccurate, with the effects of the virus not completely mirroring what was occurring in patients.
Genomic sequencing has shown that infection of conventional cell lines can immediately modify the SARS-CoV-2 virus, because it adapts to growth in these cells.
University of Melbourne Professor Elizabeth Vincan, a Laboratory Head at the Doherty Institute and lead investigator on the paper, instead looked to human organoids, a primary culture system much closer to human tissue.
“Cell lines have long been used by virologists however they are limited because ultimately they don’t model the reaction of a normal epithelial cell to infection,” Professor Vincan explained.
“As organoids are tiny, three-dimensional tissue replicas derived from stem cells - miniaturised and simplified versions of organs – we purported that they would mirror the real cells more closely”
Also importantly, the organoids are human tissue-derived and the way that SARS-CoV-2 enters the organoid cells is the same as in human tissue. Viral entry into conventional cell lines is often not the same.
“We had already been considering testing SARS-CoV-2 infection in human liver organoids, but as this was a respiratory disease, we thought we could go one better and use nasal epithelial organoids which have the same cell types as real tissue – including ciliated cells and mucous producing cells,” Professor Vincan said.
“Once the organoids are established, we can see beating cilia and mucous production by looking down the microscope.”
Collaborating with Dr Shafagh Waters team at the University of New South Wales, Sydney, Professor Vincan’s team were able to successfully grow nasal epithelial organoids which they then infected with SARS-CoV-2.
What they discovered was that infecting the nasal organoids with the ancestral Wuhan strain of SARS-CoV-2 did not cause any obvious damage to the cells. However, infection with the Delta variant caused large syncytia, where cells fuse together.
University of Melbourne Dr Bang Tran, a Postdoctoral Researcher in Professor Vincan’s lab who performed the microscopy noted that the epithelium looked battered after infection with Delta.
“We saw first-hand when we infected these cells with Delta, the damage it causes to the epithelium, we were successfully mirroring infection of the human nose,” Dr Tran explained.
“We think Delta is so much more transmissible than the ancestral Wuhan strain because it causes so much damage to the nose epithelium.”
These nasal epithelial organoids can now serve as pre-clinical models without the need for invasive collection of tissue samples or timely clinical trials, with the organoids established from a simple swab of the nasal cavity, the same technique that is used to perform a COVID-19 PCR test.
“The drug hydroxychloroquine which had performed incredibly well in conventional cell lines at stopping SARS-CoV-2 infection, did not prevent infection of organoids and failed human clinical trial,” Professor Vincan said.
“Had we tested the drug in organoids in the first place, it would not have been considered as a treatment for COVID-19.”
Professor Vincan thanked the close collaboration with Dr Waters and many researchers at the Doherty, especially Dr Samantha Grimley, Professor Joe Torresi and Dr Georgia Deliyannis.
This work was made possible with the generous donation from the Kim Wright foundation.