COVID-19 interview with JAX President Edison Liu
Dr. Liu talks scientifically about the origins of the virus that causes COVID-19. He also describes how a mouse model was developed to enable research into the disease.
SARS-CoV-2 is a coronavirus that’s newly capable of infecting humans, and it causes a disease named COVID-19. Since the initial COVID-19 cases were identified in Wuhan, China, in late 2019, it has spread to other areas of China and around the globe. Although the vast majority of confirmed cases are still within China and many of those infected experience mild symptoms, if any, the concern is growing that a global pandemic is possible.
Coronaviruses are a large group of RNA viruses, and scientists have identified hundreds of such viruses to date. They are named “corona” (like a crown) because their membranes are studded by spike-like proteins. They have been known to be infectious for decades but were initially recognized for only mild illnesses such as the common cold.
A concern regarding coronaviruses is that they are zoonotic, meaning they can spread from animals to humans and take more virulent forms. The animal source has not yet been confirmed, but in the previous 20 years, there have been two coronavirus outbreaks arising from bat-to-human transmission that infected thousands of people. Severe acute respiratory syndrome (SARS) emerged in 2002 and the Middle East respiratory syndrome (MERS) was first reported in 2012. Both SARS and MERS had higher mortality rates than COVID-19 but spread through human-human transmission more slowly.
An important first step is to characterize the virus and track how it can change and mutate over time. The good news is that modern research technologies provide the ability to do both quickly and easily, including generating genome sequences as the virus spreads. The sequences started becoming available in January, very soon after the outbreak was first recognized, and they have provided a vital first step for determining how to design vaccines and therapies.
The usual first step for the drug approval process is to test them in mice. Unfortunately, the previous outbreaks showed that the spiky coronavirus proteins that bind readily with a particular human protein to enter cells do not bind well with the mouse counterpart. The solution was to introduce the human version of the gene that codes for the protein into special "transgenic" mice. Subsequent research showed that the first SARS virus did bind well with the transgenic (human) proteins in the mice and efficiently infected them. The latest research in the field has further shown that SARS-CoV-2 binds with the same human protein to enter cells, meaning that the mouse developed for a previous outbreak may play a critical role in the one facing us now. In a few months, The Jackson Laboratory (JAX) expects to begin distributing these transgenic mice, originally developed by Stanley Perlman at the University of Iowa, for research into coronavirus infection.
JAX doesn’t have the biosafety facilities necessary to research highly infectious diseases like COVID-19. However, integral to its mission, it is currently using its expertise and mouse husbandry ability to as rapidly as possible. It will distribute them "at-cost" to infectious disease research facilities globally in the hope of providing the research and clinical communities with the resources needed to stem the current outbreak.
Mouse models play a critical role in both vaccine and drug development. Studies have shown that SARS-CoV enters the human body by binding to human angiotensin-converting enzyme 2 (ACE2). However, due to structural differences in mouse ACE2 compared to human ACE2 proteins, the SARS coronaviruses exhibit poor tropism characteristics for mouse tissues and are inefficient at infecting mice. As a result of this poor viral tissue tropism in mice, commonly used wild-type mouse strains are not optimal for studying infections of the newly discovered coronavirus. to fill the unmet need for an in vivo experimental platform for COVID-19 research.
Preliminary data, from multiple independent research institutions that have recently received cohorts of hACE2 mice from JAX, indicate that the mice are not only capable of infection by SARS-CoV-2, but also lose body weight as a result of a sustained infection that is lethal in these mice. This is similar to the results from previous research seen with SARS-CoV infection. High titers of virus were found in the lungs, brain, kidney, liver and spleen of the infected mice. Gross pathology of the lungs indicates lesions as a result of infection. None of the uninfected control mice show any signs of illness, and these mice are still alive, gaining weight and looking normal.
What is a mouse model?
The ability to model human disease in the mouse makes it such a valuable experimental system. Genetically and genomically, the human and the mouse are very similar.