Fig. 6: Schematic representation of PB2 mutations during H5N1 virus transmission. | Nature Communications

Fig. 6: Schematic representation of PB2 mutations during H5N1 virus transmission.

From: Emergence of mammalian-adaptive PB2 mutations enhances polymerase activity and pathogenicity of cattle-derived H5N1 influenza A virus

Fig. 6: Schematic representation of PB2 mutations during H5N1 virus transmission.

The schema highlights two significant H5N1 outbreaks associated with the PB2 M631L substitution: the 2013–2014 Cambodia and Vietnam outbreak and the ongoing 2024–2025 North American outbreak. During the North American H5N1 outbreak, transmission within cattle herds resulted additional adaptive substitutions (Q591R, I647V, G685R, D701N, D740N), together with the PB2 631L. Additionally, the K736R substitution was identified in H5N1 viruses infecting cats. The co-occurrence of 631L and E627K (M631L + E627K) has also emerged in cattle herds in 2025. The mutations E627K, Q591R, and D701N are well-known mammalian adaptive mutations, while I647V, G685R, and K736R represent newly discovered mammalian adaptive mutations in this study. These mutations further enhance viral polymerase activity in mammalian cells and increase viral pathogenicity in mice, posing a greater risk to mammals. Created in BioRender. lai, y. (2025) https://BioRender.com/x9td31y.

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