Largest viral-protein library gives researchers new way to probe emerging pathogens
To prevent viruses from sickening or killing us—whether it's an individual case of hepatitis B or a COVID pandemic—it's crucial to understand how the proteins they make initiate changes in our bodies ...
To prevent viruses from sickening or killing us—whether it's an individual case of hepatitis B or a COVID pandemic—it's crucial to understand how the proteins they make initiate changes in our bodies that allow them to flourish. A new tool has broadened the scale at which researchers can study these proteins, promising to speed basic discoveries in virology, inform the development of new vaccines and treatments, and help humanity protect against emerging pathogens.
The tool, called a viral ORFeome and described July 2 in an article published in the journal Cell, is the largest of its kind and enables analysis of many thousands of viral proteins in a single experiment. Its design also expands access for biologists who didn't train in virology.
"This library reveals how viruses manipulate human cells on a scale that simply wasn't possible before," said senior author Stephen Elledge, the Gregor Mendel Professor of Genetics and of Medicine at Harvard Medical School and Brigham and Women's Hospital, whose team led the creation of the tool.
"We believe it changes virology from studying one virus at a time to discovering the common strategies and surprising innovations that viruses have evolved, providing a powerful new foundation for understanding emerging viral threats," he said.
The paper shows how the team has already used the ORFeome to identify hundreds of viral proteins that interfere with immune responses. In a second paper, published July 9 in Science, Elledge and colleagues delve into new insights it has revealed into how viruses hijack cells' garbage-disposal systems to evade immune attack.
The largest viral-protein library yet
It's estimated that nearly 300 kinds of viruses can harm humans. But most of them—along with the proteins they produce—aren't well studied. Scientists tend to focus on a small subset of these viruses, often because they're medically significant (like influenza) or serve as good models for understanding larger groups of viruses (like rabies as a stand-in for all rhabdoviruses).
The ORFeome and other ORF libraries like it are named after open reading frames, the technical term for DNA sequences that encode proteins. Previous viral ORF libraries from other groups focused on individual viruses or virus families and contained perhaps 100 or 200 sequences each, the authors said. The new ORFeome contains about 13,000 physical DNA sequences, or constructs, that code for about 9,000 proteins from 513 different viruses, from the Andes hantavirus to Ebola virus to Zika virus.
"Most viruses have never been studied in detail, yet evolution has already performed countless experiments for us. This library gives us a way to read the results of those experiments across the viral world," said Elledge, who is also a Howard Hughes Medical Institute Investigator.
The viruses included in the library were selected because they're known to infect humans or because they are close relatives that infect animals and could become a threat to humans.
(The ORFeome itself is harmless; the proteins it contains can't rebuild any of the original viruses, replicate themselves or infect cells. The team also followed strict federal guidelines when working with a biotech company to synthesize the DNA sequences.
"This is a biosafe way to study viral proteins individually instead of studying a whole virus," said Caleb Glassman, HMS research fellow in medicine at Brigham and Women's in the Elledge Lab, co-author of the Cell paper and first author of the Science paper.)
A new ORF library from a separate team, reported in the same issue of Cell and dubbed the eORFeome, takes the field a step in another direction by including nearly 4,000 sequences from viruses, bacteria and parasites.
Researchers can take anywhere between one and all 13,000 DNA constructs in Elledge and colleagues' viral ORFeome and insert them into cell cultures so that each cell receives instructions for making a single viral protein. Researchers can then investigate which proteins affect a cellular function—such as camouflaging the cell from immune attack, disrupting metabolism or prioritizing viral replication—and how they do it.
"Once you have this library, you can start looking at how viruses interact with all kinds of different cell processes," said Colin O'Leary, HMS research fellow in medicine at Brigham and Women's in the Elledge Lab, co-first author of the Cell paper and co-author of the Science paper.
The results could point researchers to human or viral proteins, genes or processes that could be disabled—or augmented—to fight infection, whether through a vaccine or an antiviral drug. If the tool reveals that multiple viruses employ the same specific tactic, that could aid in the development of therapies that protect against more than one disease, O'Leary said.
Genetic barcoding and other advantages
The team attached a unique ID tag known as a genetic barcode to each ORF, allowing researchers to conduct studies of all 13,000 ORFs at once and keep track of each one.
"We can insert the sequences into a population of cells, ask questions like which ones cause the cells to grow better or worse, and then identify those by their barcodes when the experiment is finished," said O'Leary. "It hasn't been possible before to do genetic screens like this with viral proteins."
The team will make the ORFeome freely available for scientists to use. Elledge and colleagues gave it a flexible design so researchers can apply it to different model systems and types of tests.
"We designed it so biologists who aren't virologists can use it," said Glassman. "A big advantage is that we have a unified resource that's compatible with common laboratory workflows."
Revealing unseen functions in virology
To demonstrate the tool's capabilities, the team conducted genetic screens in three cell types, looking for viral proteins that affect cell proliferation, stop cells from presenting antigens on their surfaces that trigger the immune system to attack, or block the effects of interferon, a substance that prompts nearby cells to raise defenses against infection.
They found more than 700 viral proteins that contribute to at least one of those actions. Many of those proteins hadn't been studied before. Some had been studied but weren't known to have these particular functions.
The team also discovered that some viral proteins perform actions scientists wouldn't have predicted based on their structures and genetic sequences, O'Leary said. This demonstrates the value of ORF libraries representing actual viral proteins compared with libraries that contain sequences computationally predicted to have certain functions, the authors said.
In the Science paper, the team focused on identifying viral proteins that activate a cellular garbage-disposal system known as the ubiquitin proteasome to get rid of host-cell proteins that could hinder the virus.
"Viruses have to act super quickly to ensure the cell doesn't realize they're there," Glassman explained. "They plug into the ubiquitin proteasome system to degrade certain proteins so they can go about copying themselves and hiding from the immune system."
Glassman and colleagues built a list of viral proteins that remove host proteins and documented the parts of the proteasome they act on, as well as the host-cell proteins they trash. In doing so, the team discovered new strategies viruses employ.
"They're using the ubiquitin proteasome system in diverse and innovative ways while tending to target early steps in host pathways that sense and block infection," Glassman said.
For example, they found that a protein called NSP1, made by a rotavirus that causes intestinal illness, remixed host genes to make a ubiquitin-modifying complex rarely observed in host cells.
Uncovering things that viruses make or do that host cells don't opens opportunities to design drugs that hinder viral activity while sparing normal function, the authors said.
The team looks forward to more discoveries the ORFeome has the potential to power. Proteins can be added as new viruses emerge—a phenomenon that recent history has demonstrated all too well.
When O'Leary began his Ph.D. studies in the Harvard Kenneth C. Griffin Graduate School of Arts and Sciences through the Program in Virology, there was an Ebola epidemic in West Africa and a Zika outbreak in South and Central America.
"It convinced me that viruses are very important to study and understand," O'Leary said.
Publication details
Eric Fujimura et al, A viral ORFeome library for systems-level genetic dissection of host-pathogen interactions, Cell (2026). DOI: 10.1016/j.cell.2026.05.024
Caleb R. Glassman et al, Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion, Science (2026). DOI: 10.1126/science.aec6299
Tomas Pachano et al, Systematic discovery of pathogen effector functions across human pathogens and pathways, Cell (2026). DOI: 10.1016/j.cell.2026.06.017
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Citation: Largest viral-protein library gives researchers new way to probe emerging pathogens (2026, July 10) retrieved 11 July 2026 from https://phys.org/news/2026-07-largest-viral-protein-library-probe.html
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