INFLUENZA D virus can efficiently infect human respiratory cells while largely evading early immune detection, raising concerns that it may have the potential to spill over into humans with only minimal evolutionary change. Although primarily found in livestock such as cattle and swine, this virus has been increasingly studied due to evidence of exposure among agricultural workers.
Influenza D Virus in Human Airway Cells
Researchers investigated multiple influenza D virus isolates collected from livestock between 2011 and 2020 to assess their ability to infect human airway systems. Using advanced laboratory models that mimic the human respiratory tract, including lung epithelial cells and precision-cut lung tissue samples, the virus was shown to replicate effectively in human-derived tissues. In some cases, replication levels were comparable to those seen with seasonal human influenza A virus.
Efficient Replication but Weak Early Immune Detection
A key finding was that influenza D virus triggers a relatively weak early immune response in human respiratory cells. Specifically, it showed reduced activation of interferon signalling pathways, which normally help the body detect and respond to viral infections. This resulted in lower production of antiviral signals and immune-stimulating molecules compared with human influenza viruses.
However, once an antiviral state was artificially induced, the virus became more vulnerable, suggesting it is not fully resistant to immune defences but may initially evade detection during early infection stages.
Implications for Zoonotic Spillover Risk
The ability of the virus to replicate efficiently in human airway tissues while limiting early immune recognition is a concerning feature from a public health perspective. These characteristics are often associated with viruses that have the potential to cross species barriers.
Importantly, the findings suggest that only small genetic changes might be needed for influenza D virus to achieve more sustained transmission in humans, although this has not yet been observed.
Need for Enhanced Surveillance
The study highlights the importance of monitoring influenza viruses circulating in livestock populations. People in regular contact with cattle and swine may already be exposed, as suggested by reported antibody responses in occupational groups.
Overall, the research underscores the need for further surveillance and investigation into influenza D virus, particularly at the animal–human interface, to better assess its pandemic potential before widespread human adaptation occurs.
Featured image: Serhii on Adobe Stock
Reference
Sanders CG et al. Efficient replication of influenza D virus in the human airway underscores zoonotic potential. Proc Natl Acad Sci U S A. 2026;123(17):e2530325123.
