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#Synergy between HA #cleavage site #sequence and NA-mediated #plasminogen recruitment as a virulence mechanism for low-pathogenic avian #influenza

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By G.M.

 


ABSTRACT

An outbreak of H3N1 low-pathogenic avian influenza virus (LPAIV) in Belgium in 2019 caused unexpected levels of mortality and morbidity in poultry. These viruses possess an NA polymorphism associated with plasminogen (PLG) binding, as well as an atypical sequence around the HA cleavage site; accordingly, HA cleavage mediated by NA-driven PLG recruitment has been proposed to underlie their systemic spread and pathogenicity. To test this, we established a reverse genetics system for A/chicken/Belgium/460/2019 and created single mutations in HA (K345R) and NA (S122N) that restored the viruses to normal consensus, as well as an HA/NA double mutant. Confirming previous work, trypsin-independent spread and HA cleavage of wild-type Ck/Belgium were observed in the presence of fetal bovine serum containing PLG in vitro. Dose-dependent HA cleavage and trypsin-independent spread were also observed in the presence of purified chicken PLG. Compared to the wild-type virus, both HA cleavage and virus spread in vitro were reduced by the HA K345R mutation and further blocked by the NA mutation S122N. PLG-mediated HA cleavage was seen in a variety of avian cell lines and chicken organoids, excluding cell type-dependent effects. Furthermore, in ovo tests showed that mutant viruses unable to recruit PLG were less able to replicate systemically in chicken embryos. Bioinformatics analyses revealed other viruses that could potentially recruit PLG, including two independent outbreaks of H6N1 viruses, one of which we confirmed PLG-driven spread in vitro. We conclude that PLG recruitment by NA is a general virulence mechanism of N1 LPAIVs.

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Link: https://journals.asm.org/doi/full/10.1128/mbio.02466-25?af=R

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