Mice with human receptor for coronavirus provide a faster way to test vaccines.
A remedy for Middle East respiratory syndrome (MERS), the coronavirus outbreak from Saudi Arabia that has killed 77 of the 180 people who have contracted it, has so far eluded researchers. But they have now created the first mouse model of the disease, which could enable faster testing of drugs and vaccines. The method used to make mice susceptible to MERS might also provide a quick way to study future pandemic viruses in mice.
The coronavirus infects humans by binding to a protein, called DPP4, that sits on the surface of cells in the lungs. But the structure of the mouse version of DPP4 is different and the virus does not bind to it. The virus does infect macaques and marmosets, which develop a mild form of the disease, and researchers have begun using them to test vaccines and drugs. Yet working with monkeys is expensive and slow.
To create a more practical model, Stanley Perlman, a microbiologist of the University of Iowa in Iowa City, and his colleagues put the gene encoding human DPP4 into an adenovirus to which mice are susceptible. They exposed the mice to the adenovirus — similar to a cold virus — through inhaled droplets that entered their lungs. Once the adenovirus had invaded cells in the lungs, the cells began making the human DPP4 protein and expressing it on their surfaces.
When the researchers then had the mice inhale droplets containing the MERS coronavirus, the coronavirus bound to the human receptor and began taking over the cells. “The animals are walking around as bags of viruses,” said Perlman, in a 29 January presentation at a meeting of the American Society for Microbiology in Washington DC. The animals’ immune systems responded and made antibodies to attack the MERS virus. The mice never became sick or lost weight, however, which is something of a mystery, says Perlman, although he points out that it is not unusual for human viral diseases to have milder effects in mice.
Shibo Jiang, a viral immunologist at the New York Blood Center in New York, is impressed with the study and says that there is a great need for a small animal model for MERS. At the meeting, he presented an approach to developing a MERS vaccine after his laboratory discovered a rod structure on the surface of the coronavirus that binds to DPP4 and can be used to activate the immune system1. Jiang’s group plans to begin testing the vaccine in Perlman’s new mouse model.
Virologist Bart Haagmans at Erasmus Medical Center in Rotterdam, the Netherlands, says that a better animal model would be a transgenic DPP4 mouse, with the gene encoding DPP4 integrated into its genome. That would allow researchers to avoid having to infect a mouse with the adenovirus for every experiment. Additionally, he says, it is not known whether the adenovirus targets the same types of cells in the mouse lungs as it does in humans. This could affect the progression of the disease and immune response.
Charles Rice, a virologist at Rockefeller University in New York, says that Perlman's work confirms that the presence of the human DPP4 protein allows mice to be infected, and is important to know before going through the trouble of making a transgenic mouse. In 2011, Rice’s laboratory used an intravenously injected adenovirus to deliver genes encoding human factors necessary for hepatitis C virus entry into mice2. Hepatitis C had also previously lacked a good mouse model.
Perlman says that his lab is working on a transgenic DPP4 mouse, a process that can take years. He adds that although such a model might be more exact, the inhaled-adenovirus method is special in that it could theoretically be used to make a mouse model for any new human airborne virus, and would take only a few months.
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Reardon, S. Biologists make first mouse model for MERS. Nature (2014). https://doi.org/10.1038/nature.2014.14634