Abstract
H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy. These viruses cause systemic infection in poultry and accidental human infection leads to severe pneumonia, associated with high mortality rates. The hemagglutinin (HA) of H5N1 HPAIV possesses multiple basic amino acids, as in the sequence RERRRKKR at the cleavage site; however, the role of this motif is not fully understood. Here, we showed that a 33-amino acid long peptide derived from HA of H5N1 HPAIV (HA314-46) has the potential to penetrate various cells and lung tissue through a sialic acid-independent endocytotic pathway. Mutant peptide analyses revealed that the cysteine residue at position 318 and multiple basic amino acids were essential for the cell-penetrating activity. Moreover, reassortant viruses possessing H5 HA could enter sialic acid-deficient cells, and virus internalisation was facilitated by cleavage with recombinant furin. Thus, our findings demonstrate that the HA314-46 motif exhibits cell-penetrating activity through a sialic acid-independent cell entry mechanism.
Highlights
H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy
We demonstrated that HA314-46, 33-amino acids in the C-terminus of H5N1 HPAIV HA1 protein, functioned as a cell-penetrating peptides (CPPs) in vitro and in vivo
We demonstrated that HA314-46 activity might contribute to H5N1 HPAIV entry through sialic acid-independent endocytotic pathway
Summary
H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy These viruses cause systemic infection in poultry and accidental human infection leads to severe pneumonia, associated with high mortality rates. In contrast with the HA proteins of low pathogenic viruses, the HA proteins of H5N1 HPAIVs contain multiple basic amino acids at the cleavage s ite[12] This characteristic sequence is cleaved by ubiquitous cellular proteases, such as furin and proprotein convertase 6 13,14, suggesting systemic infection in p oultry[15]. The HA cleavage site motif of H5N1 HPAIV resembles cationic cell-penetrating peptides (CPPs) such as trans-activator of transcription (TAT) from human immunodeficiency virus type 1 (HIV-1)[16].
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