Now, a team of researchers from the UCSF Quantitative Biosciences Institute (QBI), Icahn School of Medicine at Mount Sinai, Institut Pasteur, and Fred Hutchinson Cancer Center has identified a remarkably small genetic difference that may help explain how some animal viruses adapt to humans and cause serious illness.

Their findings, published in Cell Host & Microbe, show that changing just one amino acid in a coronavirus protein can alter how the virus interacts with the immune systems of both bats and humans, leading to very different responses to infection.

Tiny Genetic Change, Major Biological Effects

To investigate the process, researchers compared SARS-CoV-2 with RaTG13, a closely related coronavirus that infects bats but has not been known to infect humans.

The team examined how each virus interacted with immune proteins in both human and bat lung cells. The work was made possible by the first laboratory-grown lung cell line developed from the greater horseshoe bat.

One viral protein, known as OrfB9, stood out as particularly important. Although the SARS-CoV-2 and RaTG13 versions of OrfB9 are nearly identical, they differ by just one amino acid among roughly 100 amino acids in the protein.

Different Responses in Human and Bat Cells

That tiny difference produced strikingly different effects.

In human lung cells, the SARS-CoV-2 version of OrfB9 shut down an important immune alarm system, allowing the virus to replicate more effectively.

In bat lung cells, however, the RaTG13 version activated an immune protein that helped keep the virus under control.

The findings suggest that even extremely small genetic changes can influence whether a virus remains confined to its natural animal host or gains the ability to thrive in humans.

"The difference between a virus that stays in bats and one that spills over into humans and causes catastrophic disease can come down to remarkably small genetic changes," said Nevan J. Krogan, PhD, director of QBI and senior author of the study. "By mapping these interactions at the protein level -- across two viruses and two species -- we can read the molecular signatures that predict spillover risk. It's the kind of early warning system the world needs."

Understanding Future Spillover Risks

The research provides new insight into the molecular changes that can help animal viruses adapt to human hosts. By identifying specific protein interactions linked to spillover events, scientists may be able to better recognize viruses with the potential to jump species before they trigger future outbreaks.

Authors: UCSF authors are Jyoti Batra, PhD; Yuan Zhou, MS; Rithika Adavikolanu; Durga Anand; Sooraj Verma; Martin Gordon, MS; Shivali Malpotra, MS; Jack M. Moen, PhD; Ajda Rojc, MS; Atoshi Banerjee, PhD; Sourobh Maji, PhD; Monita Muralidharan, PhD; Helene Foussard, PhD; Irene P. Chen, PhD; CJ San Felipe, PhD; Lorena Zuliani-Alvarez, PhD; Promisree Choudhury, PhD; Kirsten Obernier, PhD; Rahul Suryawanshi, PhD; Taha Y. Taha, PhD, PharmD; Kliment A. Verba, PhD; James S. Fraser, PhD; Robert M. Stroud, PhD, MA; Melanie Ott, MD, PhD; Ben Polacco, PhD; Danielle L. Swaney, PhD; Ignacia Echeverria, PhD; and Manon Eckhardt, PhD. For all authors see the paper.

Funding: National Institutes of Health (U19AI135990, U19AI135972, U54AI170792, F31AI164671-01, G20AI174733, UL1TR004419, S10OD026880, S10OD030463); Howard Hughes Medical Institute; James B. Pendleton Charitable Trust; Roddenberry Foundation; P. and E. Taft; Gladstone Institutes; Fast Grants; Innovative Genomics Institute; Chan Zuckerberg Biohub -- San Francisco; ANR EmerCoV AAP CE35.