Most pandemics begin when a virus or other pathogen is transmitted from animals to humans. Many scientists believe this is how COVID-19 emerged. SARS-CoV-2, the virus that causes the disease, is closely related to coronaviruses found in bats.
Now, a team of researchers from the UCSF Institute for Quantitative Biosciences (QBI), the Icahn School of Medicine at Mount Sinai, the Pasteur Institute, and the Fred Hutchinson Cancer Center has identified surprisingly small genetic differences that may help explain how some animal viruses adapt to and cause serious disease in humans.
Their findings were; Cell hosts and microorganismshave shown that changing just one amino acid in a coronavirus protein can change the way the virus interacts with the immune systems of both bats and humans, leading to very different responses to infection.
Small genetic changes, big biological effects
To investigate this process, researchers compared SARS-CoV-2 to RaTG13, a closely related coronavirus that infects bats but is not known to infect humans.
The research team looked at how each virus interacted with immune proteins in both human and bat lung cells. This research was made possible by the first laboratory-grown lung cell line developed from the northern spotted bat.
One viral protein, known as OrfB9, stands out as particularly important. The SARS-CoV-2 and RaTG13 versions of OrfB9 are nearly identical, but differ by just one amino acid out of approximately 100 in the protein.
Different responses of human and bat cells
That slight difference produced a surprisingly different effect.
In human lung cells, the SARS-CoV-2 version of OrfB9 shuts off a critical immune alarm system, allowing the virus to replicate more effectively.
But in bat lung cells, the RaTG13 version activated immune proteins and kept the virus under control.
The findings suggest that even extremely small genetic changes can influence whether a virus becomes restricted to its natural animal host or gains the ability to replicate in humans.
“The difference between a virus that persists in bats and one that infects humans and causes devastating disease can come down to surprisingly small genetic changes,” said Dr. Nevan J. Krogan, director of QBI and senior author of the study. “By mapping these interactions across two viruses and two species at the protein level, we can read molecular signatures that predict spillover risk. This is the kind of early warning system the world needs.”
Understand future spillover risks
This study provides new insights into the molecular changes that help animal viruses adapt to human hosts. By identifying specific protein interactions associated with spillover events, scientists may be able to better recognize viruses that have the potential to jump species before they cause future outbreaks.
author: The UCSF author is Dr. Jyoti Batra. Zhou Yuan, MS; Rishika Adavikolanu. Durga Anand. Sooraj Verma. Martin Gordon, Mississippi. Shivali Malpotra, Mississippi. Dr. Jack M. Moen; Ajuda Loyk, Mississippi. Dr. Atoshi Banerjee; Dr. Surob Majhi. Dr. Monita Muralidharan. Dr. Hélène Hussard. Dr. Eileen P. Chen. Dr. CJ Sanfelipe; Dr. Lorena Zuliani-Alvarez. Promisor Dr. Chowdhury. Dr. Kirstin Obernier. Dr. Rahul Suryawanshi. Taha Y. Taha, Ph.D., Pharm.D. Dr. Climent A. Verba. Dr. James S. Fraser. Dr. Robert M. Stroud, MA; Melanie Ott, MD. Dr. Ben Polacco. Dr. Daniel L. Swaney. Dr. Ignacia Echeverría. and Dr. Manon Eckhart. See paper for all authors.
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 Institute; Rapid Grant; Institute for Innovative Genomics; Chan Zuckerberg Biohub — San Francisco; ANR EmerCoV AAP CE35.
