A new study shows that the influenza D virus, which has been flying around inconspicuously since it was detected in animals in 2011, may be actively making copies of itself in human cells and lung tissue samples, researchers said.
The findings suggest there is a strong potential for influenza D to spread to humans, the scientists said. Some people who work with cattle, which are thought to be the main host for this virus, have been found to have influenza D antibodies in their blood, but no active infection in humans has been found to date.
The results showed that several genetically distinct influenza D strains isolated from other animal hosts, cows and pigs, were as effective at replicating in cells from the human respiratory tract as influenza A viruses, a type of influenza associated with both modern seasonal diseases and historic pandemics.
All viruses had similar replication abilities within these human cells and tissues, despite their genetic distance from each other. ”
Cody Warren, first author, assistant professor of veterinary life sciences, The Ohio State University
“There appear to be many animal species susceptible to influenza D viruses, suggesting that different hosts may evolve differently. What is clear is that a zoonotic disease is occurring.
“If we are actually on the verge of seeing it, this is an opportunity to invest in monitoring and basic understanding of its biology so that we can be prepared if it emerges in the future.”
This week, the study Proceedings of the National Academy of Sciences.
The swine influenza D virus used in this study was collected as part of long-term surveillance of swine influenza, the influenza A virus, at county and state fairs led by Andrew Bowman, a professor of veterinary medicine and preventive medicine at The Ohio State University.
“The detection of influenza D in the samples raises the question of what the risks are at human-animal interfaces,” said Bowman, a co-author of the study.
“The current belief is that cattle are the natural host for influenza D. So we don’t know if pigs are a secondary host. The fact that pigs were infected is what we were trying to understand. Is that a potential pathway for the virus to adapt to a virus that is more transmissible in humans? So the pig element is trying to understand the role of pigs against influenza D.”
Warren’s lab began by testing influenza D replication in cells that mimic human airways by differentiating patient-derived lung epithelial cells at the air-liquid interface, the cellular conditions that the virus would naturally encounter.
“When the virus started replicating in those cells, similar to influenza A, we decided to take advantage of another physiologically relevant system to assess the wide range of cell types, or tissues, that this virus targets,” Warren said.
The research team compared the growth of influenza types D and A in both human and pig lung tissue and found that both virus types replicated efficiently in lung tissue of both species.
Cell and tissue experiments also showed important differences between the two influenza types. Despite replicating well, influenza D did not stimulate a strong antiviral immune response in infected cells, whereas influenza A virus did.
Separate tests in cell culture showed that influenza D proliferation was restricted when cells were first stimulated with the protein interferon, suggesting that human cells are equipped with powerful mechanisms to limit viral infection.
In infected animals, influenza D causes respiratory symptoms that the cows and pigs recover from, suggesting that their immune systems are protecting them from infection. In humans, most viral infections trigger the release of interferon, which causes inflammation and increases body temperature, causing symptoms that make you feel sick.
These initial findings raise an important question: Did people get infected without getting sick, meaning that influenza D is not a serious health risk? Or are they so stealthy that they can hide from the immune system, leaving us unable to fight them?
“Those are gaps that we don’t fully understand,” Warren said. “This virus replicates to very high levels, but it doesn’t elicit a strong interferon response. Does it behave differently in the human body than in these cell- or tissue-based systems? That’s debatable.
“The only smoking gun we’re missing appears to be virus isolated from humans. There’s evidence of a history of exposure, but not necessarily an indication of active infection.”
Professor Bowman is collecting more influenza D viruses from pigs through ongoing swine flu surveillance and plans to analyze samples to assess whether and how the virus is changing.
“The current focus on influenza D is that it has been recognized as a cause of respiratory disease in cattle, and we have certainly seen it cause disease outbreaks in pigs,” he said. “The fact that it causes disease in some host species raises some concerns about how it might affect humans. It may not cause disease in this particular form, but it may be able to in its evolved form.”
This research was supported by the U.S. Department of Agriculture, the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the Ohio State Research, Innovation, and Knowledge Enterprise.
Other co-authors include Christina Sanders, Mine Liu, Giovanna Fusco, Elizabeth Orr, Natalie Tarbuck, Emily King, Debra Huey and Amanda Panfil of Ohio State University. Thomas Fabrizio and Richard Webby of St. Jude Children’s Research Hospital; Philip Chen and Mark Peoples of Nationwide Children’s Hospital.
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Reference magazines:
Sanders, C.G. others. (2026). Efficient replication of influenza D virus in the human respiratory tract highlights its zoonotic potential. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2530325123. https://www.pnas.org/doi/10.1073/pnas.2530325123
