Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals

Authors: TURNBULL, MATTHEW - University Of Glasgow; CLARE, SIMON - University Of Cambridge; LIEBER, GAUTHIER - University Of Glasgow; STEWART, DOUGLAS - University Of Glasgow; HENDRY, SARA CLOHISEY - University Of Edinburgh; HARCOURT, KATHERINE - University Of Cambridge; PINTO, RUTE - University Of Glasgow; LEE, HUI-MIN - University Of Edinburgh; GAUNT, ELEANOR - University Of Edinburgh; HUGHES, JOSEPH - University Of Glasgow; LONEY, COLIN - University Of Glasgow; Kapczynski, Darrell; MONNE, ISABELLA - Instituto Zooprofilattico Sperimentale Del Mazzogiorno; HUTCHINSON, EDWARD - University Of Glasgow; RIHN, SUZANNAH - University Of Glasgow; BAILLIE, KENNETH - University Of Edinburgh; SMITH, KENNETH - University Of Cambridge; DIGARD, PAUL - University Of Edinburgh; WILSON, SAM - University Of Glasgow

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/22/2025
Publication Date: 11/27/2025
Citation: Turnbull, M., Clare, S., Lieber, G., Stewart, D., Hendry, S., Harcourt, K., Pinto, R., Lee, H., Gaunt, E., Hughes, J., Loney, C., Kapczynski, D.R., Monne, I., Hutchinson, E., Rihn, S., Baillie, K., Smith, K., Digard, P., Wilson, S. 2025. Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals. Nature. 390:6776. https://doi.org/10.1126/science.adq4691.
DOI: https://doi.org/10.1126/science.adq4691

Interpretive Summary: Fever is an evolutionarily conserved component of the immune response and this study highlights that elevated temperature can mediate remarkably potent anti-influenza A virus (IAV) activity, supporting the notion that fever is an ancient and potent antiviral defense. PB1 genes acquired from avian-adapted viruses enabled efficient virus replication at febrile temperatures. The 1918 H1N1, 1957 H2N2, and 1968 H3N2 pandemics were all caused by IAVs with an avian origin PB1 genes. Previous studies have highlighted the importance of host-origin in determining temperature sensitivity of IAVs. Our studies demonstrate that while fever can be a key anti-IAV defense, avian-origin PB1s can circumvent this response and considerably increase pathogenicity.

Technical Abstract: Despite fever being an evolutionarily conserved response to infection, how the febrile state impacts influenza A virus (IAV) infection is not fully understood. Avian IAVs can replicate at temperatures associated with high fever in humans, unlike human-adapted viruses which are temperature sensitive. However, the significance of this in determining pathogenicity in a febrile host has not been established. Here we use a pyrogen-independent simulated fever model to demonstrate that fever-range hyperthermia potently protects mice against a model human H1N1 virus. We reveal a role for viral polymerase subunit PB1 in shaping temperature sensitivity via a virus strain- and host-specific interaction with cellular ANP32A/B. Avian-origin PB1 genes, including those from highly pathogenic H5N1 avian influenza and the 20th century pandemic viruses, enable fever-resistant activity of human IAV polymerases. PB1 residues associated with fever-resistant replication cluster to a conserved surface of the polymerase and facilitate interaction with host ANP32A at febrile temperature. Importantly, a virus with a fever-resistant PB1 caused lethal infection in febrile mice unlike the parental virus. These novel insights could help shape the practice of suppressing fever in patients infected with IAVs, which may be detrimental for those infected with human seasonal viruses.