One Tiny Change May Explain How Viruses Jump From Bats to Humans

Scientists found that one tiny genetic change may determine whether a bat virus stays in bats or becomes a human threat.

Most infectious disease outbreaks begin when a virus or other pathogen crosses from animals into people. Many scientists believe that is how the COVID-19 pandemic began, with SARS-CoV-2, the virus responsible for COVID-19, originating from a family of coronaviruses found in bats.

Now, researchers from the UCSF Quantitative Biosciences Institute, Icahn School of Medicine at Mount Sinai, Institut Pasteur, and Fred Hutchinson Cancer Center have uncovered evidence that a single amino acid change in a coronavirus protein can dramatically alter how the virus interacts with the immune systems of bats and humans. Their findings offer new insight into how an otherwise harmless animal virus can evolve into one capable of causing serious disease in people.

The research was published in Cell Host & Microbe.

A Tiny Genetic Difference With a Big Impact

To investigate what allows some coronaviruses to infect humans, the team compared SARS-CoV-2 with a closely related bat coronavirus called RaTG13, which infects bats but is not known to infect people. Using the first laboratory-grown lung cell line developed from the greater horseshoe bat, the researchers examined how each virus interacted with immune proteins in both bat and human lung cells.

One viral protein, known as OrfB9, stood out. The SARS-CoV-2 and RaTG13 versions of OrfB9 differ by just one amino acid out of roughly 100, yet that tiny difference had striking 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 easily. In bat lung cells, the RaTG13 version had the opposite effect, activating an immune protein that helped keep the virus under control.

Clues to How Viruses Cross Species

The discovery highlights how even the smallest genetic changes can influence whether a virus remains confined to animals or gains the ability to infect 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.”

By identifying the molecular changes that alter interactions between viruses and the immune system, the researchers hope their work will improve scientists’ ability to recognize animal viruses with the greatest potential to spill over into humans before they spark future outbreaks.

Reference: “Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential” by Jyoti Batra, Magdalena Rutkowska, Yuan Zhou, Chengjin Ye, Rithika Adavikolanu, Janet M. Young, Durga Anand, Sooraj Verma, Haripriya Parthasarathy, Martin Gordon, Shivali Malpotra, Anastasija Cupic, Thomas Kehrer, Melanie Dos Santos, Ronald Benjamin, Jack M. Moen, Declan M. Winters, Vincent Caval, Ajda Rojc, Ignacio Mena, Sadaf Aslam, Carles Martinez-Romero, Isabela Conde Viñas, Zain Khalil, Keith Farrugia, Fernando Villalón-Letelier, Atoshi Banerjee, Dafna Tussia-Cohen, Amy Diallo, Sourobh Maji, Monita Muralidharan, Helene Foussard, Irene P. Chen, Rotem Fuchs, C.J. San Felipe, Lorena Zuliani-Alvarez, Promisree Choudhury, Kirsten Obernier, Ségolène Gracias, Rahul K. Suryawanshi, Boris Bonaventure, Carlos Ibáñez, Jeffrey R. Johnson, Javier Juste, Lars Pache, Robert M. Stroud, Kliment A. Verba, James S. Fraser, Harm van Bakel, Taha Y. Taha, Melanie Ott, Tzachi Hagai, Nolwenn Jouvenet, Caroline Demeret, Benjamin J. Polacco, Danielle L. Swaney, Ignacia Echeverria, Mehdi Bouhaddou, Manon Eckhardt, Harmit S. Malik, Luis Martinez-Sobrido, Lisa Miorin, Adolfo García-Sastre and Nevan J. Krogan, 13 May 2026, Cell Host & Microbe.
DOI: 10.1016/j.chom.2026.04.015

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.

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