Most pandemics start when a pathogen spreads from animals to humans. It's a leading explanation, in fact, for the COVID-19 pandemic: the SARS-CoV-2 virus, which causes COVID-19, is a cousin to coronaviruses that live in bats.
Now, researchers at the UCSF Quantitative Biosciences Institute , Icahn School of Medicine at Mount Sinai, Institut Pasteur, and Fred Hutchinson Cancer Center report that a single change in an amino acid - a building block of proteins - alters how coronaviruses interact with bat and human immune systems, shifting the body's response to infection.
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.
Nevan Krogan, PhD
The discovery helps explain how benign animal viruses can adapt to humans and cause severe disease. The study appeared in Cell Host & Microbe on May 13.
Researchers looked at SARS-CoV-2 and a related coronavirus called RaTG13, which only infects bats, and compared how each virus interacted with proteins in bat and human lung cells. The experiments relied on the first laboratory-grown lung cell line from the greater horseshoe bat.
A viral protein called Orf9b emerged as a key factor. The SARS-CoV-2 and RaTG13 versions of Orf9b are 93% identical but behave very differently. In human cells, the SARS-CoV-2 version disabled an immune alarm system, allowing the virus to multiply. In bat cells, the RaTG13 version activated a protein that helped suppress the virus.
The team found that changing just one of Orf9B's 100 amino acids reversed its ability to evade the immune system.
"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."
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.
