Identifying the mechanisms through which the new coronavirus enters and infects cells can help scientists combat COVID-19—and perhaps other emerging viruses.
Professor Adam Hoppe of the South Dakota State University Department of Chemistry and Biochemistry will identify genes that inhibit or contribute to viral infections through a one-year, $200,000 National Science Foundation grant. Hoppe is the second SDSU researcher to receive funding through NSF’s Rapid Response Research mechanism to address the COVID-19 pandemic.
The goal of the project, which began in July, is to figure out “how the coronavirus gets into cells to initiate infection,” said Hoppe, describing the work as “a very basic science approach, aimed at broadly identifying all of the cellular machinery that affects viral entry.” Hoppe, a cell biologist, is also director of the South Dakota BioSystems Networks and Translational Research center, known as BioSNTR.
For the NSF grant, Hoppe and his team of one research associate and one doctoral student will determine how each gene in the human genome affects the new coronavirus’ ability to enter the cell. The SDSU genome sequencing facility, led by professor Jose Gonzalez, will also play an integral role.
Other research groups have identified two gene-encoding proteins to which the novel coronavirus binds—ACE2 and TMPSS2. However, Hoppe said, "We will use the CRISPR gene-editing tool and an unbiased approach to identify what host cell factors either allow the virus to enter the cell or, perhaps, prevent it from entering the cell.”
What they learn may help scientists develop antivirals and therapeutics to combat COVID-19. “Our findings could have implications for coming up with prophylactics to prevent viral entry and treatments to activate some of the genes that prevent the virus from getting into the cell,” Hoppe said.
To study the severe acute respiratory syndrome coronavirus 2, Hoppe and his team will develop a pseudovirus they can work with in the lab. “We transfer the (SARS-CoV-2) spike protein, which is responsible for allowing the virus to enter the cell, onto the pseudovirus to study how the protein gains entry into the target cell,” he explained.
The researchers will then use CRISPR gene-editing tools to shut off a single gene in a human cell using a technique Hoppe developed. They then will expose the cell to the pseudovirus. “We will screen 20,000 different genes, all at once, and ask if each of their functions is associated with helping or inhibiting virus entry,” Hoppe said.
The cells they study will be human epithelial cells that line the nasal passages and the lungs, as well as immune cells called macrophages. “Macrophages are constantly cleaning debris and bacteria that get into the lungs,” explained Hoppe, noting his lab specializes in macrophage research.
“The virus does not likely replicate in these immune cells, but if the virus gets into the cytoplasm, it may change the macrophage’s ability to function—that is our hypothesis,” he said. During the 2003 SARS outbreak, researchers found the virus was able to infect the macrophages as they tried to gobble up the virus. This portion of the project will help determine if the SARS CoV-2 virus has this capability.
Through this project, Hoppe said, “We hope to learn something specific to help with COVID-19, but also to generate knowledge that is applicable to new viral infections, as well as the tools to do this type of screening for other viruses, such as influenza.”