Influenza A(H6N6) Virus now infects mammals

The Influenza A(H6N6) Virus is an avian influenza virus that has recently expanded its host range from birds to mammals. Influenza A(H6N6) Virus is one of the most frequently isolated subtypes in poultry, and it has a broad host range. Some strains can overcome species barriers for transmission and infect humans[1]. In this study, two Influenza A(H6N6) avian virus strains originating from five different clades, in which amino acid 226 of hemagglutinin was mutated from glutamine to lysine, were isolated from ducks.

You must understand that Influenza A viruses constantly mutate and it always seems that they have a mind of their own, always trying to expand their natural reservoirs, and always on the hunt for human victims.

Research has shown that some strains can now bind to human-like receptors, raising concerns about human infection. Although Influenza A(H6N6) Virus is (still) a low-pathogenic avian influenza virus (LPAIV), it is unclear whether it triggers pyroptosis in human lungs, a process linked to cytokine storms in infections like Influenza A(H7N9) Virus.

A study has now demonstrated that Influenza A(H6N6) Virus can efficiently replicate in and infect human alveolar macrophages and M1-polarized macrophages[2]. Crucially, Influenza A(H6N6) infection in M1 macrophages induces pyroptosis, a highly inflammatory form of lytic programmed cell death, via the NLRP3/Caspase-1/GSDMD pathway, which may exacerbate pro-inflammatory responses. Given that M1 macrophages naturally produce pro-inflammatory cytokines, concurrent pyroptosis—releasing substantial IL-1β and IL-18—may exacerbate pro-inflammatory responses. This cascade may trigger a pulmonary cytokine storm, which could be a mechanism underlying Influenza A(H6N6) Virus pathogenesis.

[1] Zhu et al: Characterization and Pathogenicity of Novel Reassortment H6N6 Avian Influenza Viruses in Southern China in Transboundary and Emerging Diseases – 2024. See here.
[2] Zhu et al: H6N6 Avian Influenza Virus Infection Induced Pyroptosis of M1 Macrophages by Activating Caspase-1 in Viruses – 2025. See here.