Abstract
Influenza D virus (IDV), primarily found in livestock species, has demonstrated cross-species transmission potential, yet its threat to humans remains poorly understood. Here, we curated a panel of IDV isolates collected during field surveillance from 2011 to 2020 from swine and cattle to assess their ability to infect human airway cells as a proxy for zoonotic threat assessment. Using lung epithelial cell lines, primary well-differentiated airway epithelial cultures, and precision-cut lung slices, we demonstrated that IDV efficiently propagates in cells and tissues from the human respiratory tract, reaching titers comparable to human influenza A virus (IAV). Infection kinetics in primary porcine airway cultures and respiratory tissues mirrored those from human, suggesting similar infectivity across species. To define host responses to IDV infection, we evaluated innate immune sensing and downstream interferon signaling in human respiratory cells. IDV infection resulted in markedly reduced activation of interferon regulatory factor (IRF) signaling and diminished induction of interferon lambda 1 and interferon-stimulated genes compared to IAV, indicating inefficient activation of innate immune sensing pathways. However, IDV replication was potently restricted in interferon-pretreated cells, demonstrating sensitivity to interferon-mediated antiviral effector mechanisms once an antiviral state was established. Together, these findings show that IDV can efficiently infect the human airway while limiting innate immune sensing, a feature that may facilitate zoonotic spillover. Our study highlights the need for enhanced surveillance of IDV at the animal-human interface and provides a foundation for further investigation into its biology and potential for causing human infection and disease.
Competing Interest Statement
The author E.M.K. is currently employed by AbbVie Inc. The author was not affiliated with AbbVie Inc at the time of experiment design, data acquisition, or analysis.
Funder Information Declared
United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA), 2025-39601-44639
The Enterprise for Research, Innovation, and Knowledge at The Ohio State University
Centers of Excellence for Influenza Research and Response, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Department of Health and Human Services, HHSN272201400006C, 75N93021C00016
National Institutes of Health, T35 5T35OD010977
National Institutes of Health, P30 CA016058
Source:
Link: https://www.biorxiv.org/content/10.64898/2026.02.07.704474v1
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