A research team has successfully utilized human respiratory organoids (mini-organs) to propagate human rhinovirus C (HRV-C), which had previously been refractory to conventional virus cultivation. This breakthrough opens new avenues for understanding these common respiratory viruses and expediting the development of vaccines and antiviral drugs. The findings are published in the latest issue of Nature Communications.
This milestone in virology research was achieved by a team led by Professor Jane Zhou Jie and Professor Yuen Kwok-Yung, from the Department of Microbiology under the School of Clinical Medicine in the LKS Faculty of Medicine of the University of Hong Kong (HKUMed), in collaboration with Professor Hans Clevers from the Hubrecht Institute, a pioneer in organoid technology.
HRV-C background
Human rhinoviruses (HRV), the primary pathogens for the common cold, are highly transmissible, causing upper respiratory infections throughout the year. So far, more than 160 HRV serotypes have been identified and categorized into types A, B and C; and more than 60 subtypes of HRV-C have been discovered since 2006.
HRV-C infections are generally associated with more severe symptoms and linked to the exacerbation of asthma and other chronic respiratory diseases. In the past two decades, no experimental models have been available for the large family of HRV-C due to their inability to culture in conventional cell lines in the laboratories, which has impeded research progress in developing antivirals and vaccines for HRV-C infections.
Therefore, there was an urgent need to develop new methods to culture HRV-C to develop corresponding vaccines and potent drugs to address its threat to public health. The innovative use of human respiratory organoids established by the HKUMed research team has overcome this barrier, providing a novel model system for studying and combating HRV-C.
World-first human respiratory organoids
The research team, in collaboration with Professor Hans Clevers, has dedicated seven years to establishing the world's first respiratory organoid culture system using lung adult stem cells and nasal epithelial cells. Through well-defined expansion and differentiation approaches, the team has successfully established mature nasal mucosa, airway and alveolar organoids.
The pioneering respiratory organoid culture system allows scientists to efficiently and stably reconstruct and expand the entire human respiratory epithelium in the laboratory. These award-winning biologically active respiratory organoids have become robust universal tools for studying respiratory biology and related diseases.
Research findings
The research team utilized the respiratory organoids to isolate and consecutively propagate HRV-C, followed by an in-depth characterization of virus-host interaction. They demonstrated that both airway organoids and nasal organoids are highly susceptible to HRV-C and are capable of effectively isolating the virus from clinical samples.
With immunosuppression mediated by a small molecule, airway organoids sustain serial HRV-C passage, while nasal organoids achieve this without any intervention. Moreover, nasal organoids are more sensitive to HRV-C infection than airway organoids, probably because of the stronger antiviral response of airway organoids.
Finally, the study demonstrated the application of the organoid-based HRV-C infection model for drug screening. This innovative model can therefore be utilized to develop HRV-C vaccines and antiviral drugs.
Professor Jane Zhou Jie, who led the research, highlighted the unparalleled strength of human respiratory organoids in studying HRV-C, stating, "Our study underscores the unique capacity of respiratory organoids for studying HRV-C, from reproducible propagation of the poorly cultivable virus to detailed dissection of virus-host interaction, and potential applications for developing vaccines and antivirals.
"More importantly, this study establishes a new paradigm for propagating and studying other uncultivable human viruses. The biologically active respiratory organoids enable scientists to recapitulate respiratory viral infections, evaluate drug efficacy, and develop vaccines and therapeutics to address the public health risks posed by respiratory viruses."
Professor Kelvin To Kai-wang, Chairperson and Clinical Professor from the same Department, remarked, "The breakthrough research by the team in HRV-C research showcases the Faculty's unwavering commitment to scientific innovation and provides crucial scientific support for the implementation of public health policies."
Professor Yuen Kwok-Yung, Chair Professor, also from the Department of Microbiology, emphasized, "This is a landmark study, opening a new avenue for tackling this common cold virus."