Abstract
Cleavage activation of the hemagglutinin (HA) protein by host proteases is a crucial step in the infection process of influenza A viruses (IAV). However, IAV exists in eighteen different HA subtypes in nature and their cleavage sites vary considerably. There is uncertainty regarding which specific proteases activate a given HA in the human respiratory tract. Understanding the relationship between different HA subtypes and human-specific proteases will be valuable in assessing the pandemic potential of circulating viruses. Here we utilized fluorogenic peptides mimicking the HA cleavage motif of representative IAV strains causing disease in humans or of zoonotic/pandemic potential and tested them with a range of proteases known to be present in the human respiratory tract. Our results show that peptides from the H1, H2 and H3 subtypes are cleaved efficiently by a wide range of proteases including trypsin, matriptase, human airway tryptase (HAT), kallikrein-related peptidases 5 (KLK5) and 12 (KLK12) and plasmin. Regarding IAVs currently of concern for human adaptation, cleavage site peptides from H10 viruses showed very limited cleavage by respiratory tract proteases. Peptide mimics from H6 viruses showed broader cleavage by respiratory tract proteases, while H5, H7 and H9 subtypes showed variable cleavage; particularly matriptase appeared to be a key protease capable of activating IAVs. We also tested HA substrate specificity of Factor Xa, a protease required for HA cleavage in chicken embryos and relevant for influenza virus production in eggs. Overall our data provide novel tool allowing the assessment of human adaptation of IAV HA subtypes.
Highlights
Influenza A viruses (IAV) belong to the class of Orthomyxoviridae and it is believed that waterfowl are their natural reservoir
There is evidence that the three H1 viruses have evolved from different sources, they all share the same HA cleavage site sequence (Table 1) [20,43,44]
While the 1918 and 1977 IAV strains have disappeared, the 2009 H1N1 virus is still circulating in human populations and poses a threat to public health
Summary
Influenza A viruses (IAV) belong to the class of Orthomyxoviridae and it is believed that waterfowl are their natural reservoir. There are 18 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes in nature, with H1–H16 circulating in wild birds [1,2]. Proteolytic screen of IAV HA peptide mimics analysis, decision to publish, or preparation of the manuscript
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