The devastating COVID-19 pandemic occurred when the SARS-CoV-2 virus, native to a species of bats, mutated to infect humans. The transition of a pathogen from only imperiling animals to threatening humans is called "spillover."
Investigating viruses with spillover potential could give us a head start on the next pandemic and minimize its severity. One such virus is RshTT200, discovered in Cambodian bats in 2010. RshTT200 shares 92.6% of its genomic sequence with SARS-CoV-2 and has an 85% match with COVID-19's infamous spike protein responsible for the virus's entry into human cells.
During the American Crystallographic Association's 73rd annual meeting, which will be held July 7-11 at the Baltimore Marriott Waterfront Hotel, Samantha Zepeda, from the University of Washington, will present her team's investigation into RshTT200 to prepare for the next potential spillover event. Her presentation will take place Sunday, July 9, at 4:00 p.m. Eastern in room Waterview CD.
Currently, a few factors prevent RshTT200 from infecting human cells. In order for the virus to spill over, it must first be able to bind to the human ACE2 receptor on the surface of human cells. The spike proteins of SARS-CoV-2 and RshTT200 are an 85% match, but that 15% difference is enough to reduce the latter's affinity to ACE2. The receptor binding domain in the spike protein exists in both open and closed conformations, but RshTT200 more strongly favors the closed conformation, which is incompetent for receptor binding. However, this conformational ensemble could change as the RshTT200 virus mutates.
There are several avenues that could enable RshTT200 to pose a threat to humans. With the help of our collaborators in the Starr Lab at the University of Utah, we identified a single nucleotide mutation that was sufficient to enable RshTT200 to enter cells after binding to the human ACE2 receptor. We also know that mutations that make the receptor binding domain more open also enable cellular entry with human ACE2."
Samantha Zepeda, University of Washington
To understand how viruses such as RshTT200 could infect humans, Zepeda and her team used cryo-electron microscopy to solve the spike protein structure. Once the spike proteins were understood, they built harmless, nonreplicating pseudoviruses expressing the spike proteins to investigate how RshTT200 accesses human cells.
Their work showed not only how RshTT200 could become the next pandemic but also how we could fight it.
"One of the most promising things this work shows is which antibodies are broadly neutralizing against RshTT200," Zepeda said. "In the event of an outbreak, we would already know how to stabilize the spike protein for the development of vaccines and have an idea of which antibodies could be used. This would put us months ahead compared to the knowledge that was available at the beginning of the COVID-19 pandemic."
The American Crystallographic Association, Inc. is a nonprofit, scientific organization of more than 1,000 members in more than 35 countries. The ACA was founded in 1949 through a merger of the American Society for X-Ray and Electron Diffraction (ASXRED) and the Crystallographic Society of America (CSA). The objective of the ACA is to promote interactions among scientists who study the structure of matter at atomic (or near atomic) resolution. These interactions will advance experimental and computational aspects of crystallography and diffraction. Understanding the nature of the forces that both control and result from the molecular and atomic arrangements in matter will help shed light on chemical interactions in nature.
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