Jyoti Batra peered into a petri dish containing lung cells from a greater horseshoe bat, the first of their kind grown in a lab, and saw a clue that could help predict the next pandemic. Inside those cells, a single amino acid—no bigger than a molecular speck—was quietly shaping the fate of coronaviruses, determining whether they remained harmless in bats or became dangerous to humans. This tiny switch, buried in a viral protein called OrfB9, is now emerging as a potential early warning signal for spillover risk, offering scientists a new way to read the molecular handwriting of future outbreaks.
Most pandemics begin with a leap—from animals to people. SARS-CoV-2, the virus behind the COVID-19 pandemic, is believed to have originated in bats, much like its close relative RaTG13. But while RaTG13 circulates in bat populations without infecting humans, SARS-CoV-2 made the jump with devastating consequences. To understand why, researchers from UCSF, Mount Sinai, Institut Pasteur, and Fred Hutchinson Cancer Center compared how the two viruses interact with immune systems across species, using cutting-edge models including the newly developed bat lung cell line.
The breakthrough came when they focused on OrfB9, a small but powerful viral protein. Despite being nearly identical in both viruses, OrfB9 differs by just one amino acid between SARS-CoV-2 and RaTG13. In human lung cells, the SARS-CoV-2 version of OrfB9 disables a key immune alarm system, allowing the virus to replicate unchecked. But in bat cells, the RaTG13 version does the opposite—it activates an immune protein that keeps the virus in check. This molecular Jekyll and Hyde effect shows how minimal genetic changes can have massive biological consequences.
The study, published in Cell Host & Microbe, reveals that spillover isn’t always about big mutations or dramatic shifts. Sometimes, it’s a single letter in the genetic code that tips the balance. "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, director of the Quantitative Biosciences Institute at UCSF and senior author of the study. By mapping how viral proteins interact with host immune systems across species, scientists are building a predictive toolkit—one that could flag high-risk viruses before they ignite global crises.
With support from the NIH, Howard Hughes Medical Institute, and several foundations, this research opens a new front in pandemic preparedness. Instead of reacting after the fact, scientists may soon be able to scan animal viruses for these molecular red flags—tiny mutations with outsized impacts. In a world still healing from one spillover event, the ability to anticipate the next one could be our best defense.