The human immune system has been evolving for millions of years, adapting to various environmental pressures and the ever-changing landscape of infectious diseases. Now, researchers have developed a way of holding the complexity of the immune system in the palms of their hands.
Stem cell-based lab animals called humanised mice were developed to carry human immune cells including T-cells, B-cells and immune proteins and receptors as a means of modelling infections or testing experimental drugs.
However, as Qingfeng Chen, a Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB) explains, not all humanised mice models are equally useful for studying complex infectious diseases such as COVID-19.
“As humans have unique immune cells, non-human animal models used to evaluate disease pathogenesis and therapeutics may have variable outcomes,” said Chen.
Together with groups from the Duke-NUS Medical School, Singapore and the University of Melbourne, Australia, Chen’s team embarked on a project to develop and characterise a specialised mouse model for studying COVID-19.
The researchers used an adenovirus vector to introduce human angiotensin-converting enzyme-2 (hACE2), a receptor the SARS-CoV-2 virus uses to enter and infect cells, into humanised ‘NIKO’ mice. They also transplanted human CD34+ hematopoietic stem cells into the animals to generate a human immune system.
They then exposed the hACE2 NIKO mice to a suite of SARS-CoV-2 variants alongside the original isolate and discovered that the animals showed signs of an acute immune system response, inflammation in the lungs, lung damage and the release of pro-inflammatory chemicals.
Because these effects mirror those observed in COVID-19 patients, the researchers propose that this approach allows for the swift creation of animal models to investigate both human immune responses and the development of diseases caused by emerging pathogens. For example, the animals can easily be genetically tailored to express receptors like dipeptidyl-peptidase 4 to study MERS-CoV instead.
“Humanised mice can be a powerful tool for the rapid establishment of animal models to study human immune responses and pathogenesis of new pathogens,” explained Chen. “With such a simple and accessible model, we can design, test and improve therapeutics safely.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).