May 12, 20256 | Austin, Minn. — The clock is ticking to find defenses against Crimean-Congo hemorrhagic fever. It’s a highly fatal tickborne illness whose global distribution puts 3 billion people at risk — and factors like changing global travel and weather patterns run the risk of worsening future outbreaks. The Crimean-Congo hemorrhagic fever virus (CCHFV) that causes this rare but deadly disease currently lacks any approved antiviral treatments. Fortunately, researchers are using their expertise and advanced technological tools to get a leg up in this arms race. Now, they’re finding answers about how CCHFV operates to aid the development of effective antiviral treatments to save lives and protect global health.
At The Hormel Institute, University of Minnesota, researchers in the lab of Associate Professor Bin Liu, PhD, used a powerful imaging technology known as high-resolution cryogenic-sample electron microscopy (cryoEM) to generate and analyze the first near-atomic-resolution structures of the CCHFV’s L protein, which plays a key role in the virus’s ability to make copies of itself and continue spreading. Their study revealing the findings appears in Nature Microbiology.
Since viruses aren’t able to reproduce on their own, they hijack the machinery inside cells to do this work for them. After attaching to a cell and injecting their genetic material, which contains their reproduction instructions, a virus’s host cell will take on those instructions and make new copies of the virus. Because the L protein is essential for the process of replication and transcription in CCHFV, the researchers analyzed it to better understand how the virus carries out the processes — and how this could be targeted for antiviral drug development.
Found throughout Europe, Asia, and Africa, the CCHFV can spread to humans via tick bites, or through exposure to infected blood or other bodily fluids from infected animals or people. Its wide range of symptoms can include fever, joint pain, vomiting, jaundice, red spots on the roof of the mouth, internal and external bleeding, and organ failure.
Up to half of patients hospitalized with Crimean-Congo hemorrhagic fever may not survive, according to the Centers for Disease Control and Prevention. For those who do, the recovery period is often slow, and its possible long-term effects are yet to be understood. Workers in health care and agricultural settings among infected animals tend to face the highest exposure risks.
“As global travel, climate change, and shifting ecosystems increase the risk of virus transmission from animals to people, investing in fundamental research like this strengthens our ability to respond quickly to future outbreaks. It lays the groundwork for both targeted therapies against CCHFV and potentially broader antiviral strategies against related viruses,” Dr. Liu said.
That groundwork begins by understanding what a virus needs to spread — and how we can interrupt those processes to stop it in its tracks.
“Understanding how this virus replicates at the molecular level is essential for developing effective therapies and improving outbreak preparedness,” Dr. Liu said. “It is compelling that such detailed structural insights at near-atomic resolution can directly inform antiviral drug development. The idea that visualizing the precise shape and movements of a viral enzyme can guide the design of targeted inhibitors represents a powerful and increasingly important approach for combating high-risk pathogens like CCHFV.”
Authors include Postdoctoral Associate Dong Wang, PhD, Postdoctoral Associate Ge Yang, PhD, and Dr. Bin Liu.
Read the paper: https://www.nature.com/articles/s41564-026-02319-1
Key findings:
- Using cryogenic-sample electron microscopy (cryoEM), researchers generated high-resolution structures of the Crimean-Congo hemorrhagic fever virus’s (CCHFV’s) L protein in two states: one when bound to the virus’s RNA, and one in its unbound (apo) state. The L protein is significant for the virus’s ability to replicate.
- The study’s findings provide a foundation for the structure-based design of antiviral inhibitors targeting the CCHFV’s L protein.
- The study also establishes a structural framework for understanding replication in nairoviruses, the virus family CCHFV belongs to.
- The cryoEM structures revealed the unique architectural features of the virus’s polymerase core and other features that make CCHFV both similar to and distinct from other negative-strand RNA viruses. Some aspects of its polymerase structure, for example, resemble the influenza virus. “This combination of ‘familiar yet different’ underscores how viruses can adapt a common molecular toolkit in diverse ways,” Dr. Liu said.
- The study revealed how the L protein recognizes viral RNA promoter sequences — a critical step for initiating the replication and transcription process.
- The team learned RNA binding induces physical shape changes that stabilize key catalytic elements of the L protein, helping essential chemical processes move along, which sheds light on how it becomes functionally active. “This creates a concrete blueprint for designing inhibitors that can block polymerase activity, a strategy that has been successful for other viral infections,” Dr. Liu said.
What’s next?
Now that key foundational elements in understanding CCHFV have been established with this study, a key next step in the field will be to move these structural insights to functional and translational applications.
“Now that we can visualize the CCHFV L protein polymerase at near-atomic resolution, an important priority is to identify and validate antiviral compounds that target the active site, RNA-binding regions, or conformational ‘switch’ elements revealed in these structures. This includes structure-guided drug design and screening for inhibitors that can effectively block viral replication,” Dr. Liu explained.
Also important will be capturing the L protein in action in additional states to obtain a more complete picture of how it operates — and more broadly, what it operates with.
“Future work will also focus on interactions with other viral and host factors. In infected cells, the L protein polymerase does not act alone: host proteins and possibly additional viral components may regulate its activity, stability, and immune evasion. Defining these interactions could uncover new therapeutic targets,” Dr. Liu said.
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Founded in 1942 by Jay C. Hormel and The Hormel Foundation, The Hormel Institute, University of Minnesota, advances science through research, education, and community to enhance wellbeing and extend human life. For more than 80 years, we have pursued our mission to conduct research and provide education in the biological sciences with applications in medicine and agriculture. A part of the University of Minnesota's Research and Innovation Office, The Hormel Institute partners with the region's leading biomedical research facilities, including Mayo Clinic.