The novel coronavirus outbreak has spread globally, with confirmed covid-19 patients on six continents except Antarctica. Up to now, the cumulative number of confirmed cases worldwide has exceeded 110,000, and the death toll has exceeded 4,000, of which the epidemic situation in Italy, South Korea, Iran, Japan and the United States is very serious.
To date, specific drugs and vaccines for the novel coronavirus (SARS-CoV-2) have not yet been available. I believe everyone has learned that vaccines and drugs must undergo rigorous clinical trials before they are listed to verify their effectiveness and safety. However, prior to clinical trials, relevant animal tests are also extremely important.
Not only that, but animal models also help to reveal the specific development of viral infections, including SARS-CoV-2, giving us a clearer understanding of these viruses.
In a quiet town in Maine, usa, the Jackson Laboratory in Bar Harbor is a facility that breeds experimental mice. The lab is busy breeding a fleet of genetically modified mice that scientists hope will help understand SARS-CoV-2.
"We've been overwhelmed by all sorts of requests." Cathleen Lutz, a neurobiologist in charge of the mouse library in Jackson's lab, said.
With no signs of subsidence due to the global outbreak of the novel coronavirus outbreak, Jackson Lab has received orders from about 50 labs to produce more than 3,000 experimental mice expressing the human ACE2 (hACE2) protein. Studies have shown that SARS-CoV-2 uses the receptor protein hACE2 to invade human cells, and normal mice do not seem to be easily infected with SARS-CoV-2.
In addition to the transgenic mice, a team from the Wuhan Institute of Virology of the Chinese Academy of Sciences found that rhesus monkeys can also be infected with SARS-CoV-2. Virologist S. Thompson of the Australian Animal Health Laboratory The team led by S. Vasan found that ferrets are susceptible to SARS-CoV-2.
Nature News recently published a report titled Labs rush to study coronavirus in transgenic animals — some are in short supply, reporting that laboratories are studying the new crown virus through genetically modified animals, resulting in a shortage of genetically modified animal models.
Infection experiments in animal models can provide researchers with information about SARS-CoV-2 infection, thereby elucidating the role of the immune system, the route of virus transmission, and so on. In response, David O'Connor, a virologist at the University of Wisconsin-Madison, commented: "No animal model is perfect, so we need not just one animal model, but multiples." ”
< h1 class="pgc-h-arrow-right" > rhesus monkey model</h1>
The study, led by Chao Shan, a virologist at the Wuhan Institute of Virology at the Chinese Academy of Sciences, found that rhesus monkeys infected with SARS-CoV-2 were quite mild in their condition and had no symptoms of fever, but lung X-rays showed symptoms of pneumonia similar to human COVID-19.
This was also confirmed by observational and anatomical experiments, with the researchers euthanizing two of the monkeys 3 days after infection and again 6 days later, while the remaining two monkeys were observed for three weeks. The monkeys all lost slightly weight, but did not appear to have other serious symptoms.
The researchers sought to solve another pressing question in rhesus monkeys — whether SARS-CoV-2 could potentially be hidden in some organs of ostensibly cured patients. At present, the phenomenon of nucleic acid testing and rejuvenation in discharged patients is not uncommon, and it is also a rather difficult problem.
In addition, there are indications that a violent response of the human immune system to the virus may cause patients to deteriorate or even die, and rhesus monkeys have immune systems similar to those of humans, which will help to study how the human immune system responds to COVID-19.
< h1 class="pgc-h-arrow-right" > transgenic mouse model</h1>
Experimental mice are extremely important animal models, but unfortunately, ordinary mice are not susceptible to SARS-CoV-2 infection, so specialized hACE2 transgenic mice need to be constructed. As early as the SARS outbreak in 2003, Jackson's laboratory bred hACE2 transgenic mice, but due to the sudden disappearance of SARS, the related research funding was sharply reduced, and the laboratory stopped the research.
After the COVID-19 outbreak, jackson labs quickly resumed a program to breed hACE2 transgenic mice and bred the first baby mice last week, and they plan to start providing researchers with hACE2 transgenic mouse models in May. Cathleen Lutz said: "We are already speeding up the progress, but it takes time for mice to conceive and become pregnant. ”
Jackson Labs
Michael Diamond, a viral immunologist at the University of Washington in the United States, is also waiting for the list of hACE2 mice, and his team hopes to test the effectiveness of vaccine and antibody therapy using hACE2 mice, and they will also use CRISPR technology to find genes that make mice more susceptible to infection or more resistant
While waiting, Michael Diamond and his team are developing other mouse models: They tried to use the virus as a vector to introduce the hACE2 gene into mice; in another study, they infected mice with immune system deficiencies with SARS-CoV-2.
The scientists hope that SARS-CoV-2, after repeated transmission in these mice, will be able to obtain mutations that will help it infect rodents with healthy immune systems. Michael Diamond says the method also applies to Zika virus, another pathogen that mice are not naturally susceptible to infection.
< h1 class="pgc-h-arrow-right" > animal model of SARS-CoV-2 still needs to be further developed</h1>
In fact, laboratories have applied hACE2 mouse models to SARS-CoV-2. A paper published in a preprint bioRxiv by a research team led by Qin Chuan, a virologist at Peking Union Medical College, describes the preliminary results of sars-CoV-2 infection in this model:
hACE2 mice, similar to rhesus macaques, appear to suffer only mild disease, weight loss, and signs of pneumonia, but not severely. In addition, the researchers also identified the immune response of mice infected with hACE2, which could guide the development of vaccines.
Qin Chuan said hACE2 mice will help fight SARS-CoV-2. In an unpublished study, his team found several drugs that could inhibit SARS-CoV-2 replication and reduce weight loss in animals.
Stanley Perlman, a coronavirus scientist at the University of Iowa, commented that animals with only minor infections may be useful for testing drugs and vaccines, but they may not help scientists understand more serious cases. Stanley Perlman is already considering developing other mouse models to better mimic severe CASES-19.
All in all, SARS-CoV-2-related animal models are being actively developed and are currently well achieved in animal models such as rhesus monkeys, hACE2 transgenic mice and ferrets, which will help accelerate the development of drugs and vaccines. But it's worth noting that these animal models show only mild symptoms of SARS-CoV-2 infection, and scientists still need to develop new animal models to mimic severe CASES-19 and help save critically ill patients.
Article links:
https://www.nature.com/articles/d41586-020-00698-x