A University of Wisconsin-Madison chemical engineer has received a National Science Foundation Rapid Response Research (RAPID) grant and an Early-Concept Grant for Exploratory Research (EAGER) to work on projects related to human coronaviruses.
John Yin, a Vilas Distinguished Achievement professor, is leading the projects, which include colleagues from chemical and biological engineering and the interdisciplinary Wisconsin Institute for Discovery, where Yin is a faculty member. For the RAPID project, the team will take an ecological view of these viruses to better understand how they enter cells, spread and cause varying immune responses in different individuals.
Most models of diseases like COVID-19 are based on purified virus stock. But in nature, many viruses are not particularly pure. RNA viruses, which include coronaviruses, are sloppy when they replicate themselves, resulting in lots of partial viruses, mutations and other “junk” particles. These are also known as defective interfering particles and can no longer replicate and spread themselves. On a potentially positive note, they can, however, tie up resources and make it more difficult for an active virus to spread from cell to cell.
Yin and his colleagues plan to find out if these defective interfering particles, documented previously in mouse coronaviruses, exist in human coronaviruses as well. If that’s the case, their next step may be to examine how viruses spread as a mixture of active and defective virus strains and how those particles interact with one another and with their host cells.
By understanding these relationships, it may be possible to manipulate this environment to control or slow the spread of the virus. The idea, Yin says, is to look at the viral ecosystem in ways similar to the microbiome, or the variety of bacteria in the human digestive tract. Researchers are beginning to understand that the diversity and ratio of that bacteria can have big impacts on disease and health. “That same kind of ecological thinking is much more slowly entering virology,” says Yin. “One aspect of it is an appreciation for the diversity of the products that come out of an infected cell. It’s not just a viable virus that wants to spread the infection, but there are also other products like defective particles that might actually limit the infection.”
To understand this complex system, the team will conduct a deep dive into the literature to synthesize what is known about the virus’s growth and spread before building mathematical models incorporating the ways the virus enters cells and expresses genes. The team has also obtained special permission to return to the UW-Madison campus to work safely to conduct wet lab experiments on human coronaviruses, but not COVID-19 itself.
The EAGER grant will support the development of a new kind of testing for anti-viral drugs. In the current gold-standard test, a plaque assay, researchers release a virus onto a dish of cells overlaid with a layer of semi-solid agar to force the virus to spread only to neighboring cells. But Yin, along with former graduate student Ying Zhu, found that by replacing the agar with a thin layer of flowing liquid medium, they could reduce testing time from three to five days to just a day or two and increase the sensitivity.
During this project, Yin will collaborate with Vilas Distinguished Achievement and Harvey D. Spangler Professor Michael Graham in chemical and biological engineering to determine the best conditions for testing drugs that may be effective against COVID-19.
In March, Congress appropriated $75 million to the National Science Foundation for RAPID and EAGER grants to fund projects that prevent, prepare for and respond to coronavirus, domestically or internationally. Previously, Yin spoke more in-depth about the perspective a chemical engineer brings to virology and the fight against COVID-19.
Author: Jason Daley