Abstract
Highly pathogenic avian influenza viruses (HPAIVs) evolve from low pathogenic avian influenza viruses (LPAIVs) of the H5 and H7 subtypes. This evolution is characterized by the acquisition of a multi-basic cleavage site (MBCS) motif in the hemagglutinin (HA) that leads to an extended viral tropism and severe disease in poultry. One key unanswered question is whether the risk of transition to HPAIVs is similar for all LPAIVs H5 or H7 strains, or whether specific determinants in the HA sequence of some H5 or H7 LPAIV strains correlate with a higher risk of transition to HPAIVs. Here, we determined if specific features of the conserved RNA stem-loop located at the HA cleavage site-encoding region could be detected along the LPAIV to HPAIV evolutionary pathway. Analysis of the thermodynamic stability of the predicted RNA structures showed no specific patterns common to HA sequences leading to HPAIVs and distinct from those remaining LPAIVs. However, RNA structure clustering analysis revealed that most of the American lineage ancestors leading to H7 emergences via recombination shared the same viral RNA (vRNA) structure topology at the HA1/HA2 boundary region. Our study thus identified predicted secondary RNA structures present in the HA of H7 viruses, which could promote genetic recombination and acquisition of a multibasic cleavage site motif (MBCS).
Highlights
Influenza viruses are widely distributed among animals, including humans
To test if the ability of H5 and H7 avian influenza viruses (AIVs) to acquire multi-basic cleavage site (MBCS) correlated with specific differences in the conserved RNA stem-loop (cSL) structure, we performed an analysis of the thermodynamic stability of the predicted cSL structure focusing on a region of eighty nucleotides
Our objective was to determine if a specific cSL structure pattern was found along evolutionary pathways that gave rise to Highly pathogenic avian influenza viruses (HPAIVs) emergences (‘low pathogenic avian influenza viruses (LPAIVs)-to-HPAIV’ group) and whether this cSL structure pattern was absent from evolutionary pathways leading to LPAIVs as the final phylogenetic event (‘LPAIV-only’ control groups)
Summary
Influenza viruses are widely distributed among animals, including humans. The aquatic birds, predominately of the orders Anseriformes and Charadriiformes, constitute their major natural reservoirs (Webster et al 1992). A wide variety of hemagglutinin (HA)/neuraminidase (NA) combinations of HA1-16 and NA1-9 avian influenza viruses (AIVs) are circulating among aquatic birds, especially ducks (Webster et al 1992; Vandegrift et al 2010; Wahlgren 2011). The HA cleavage site (HA-CS) motif of LPAIVs has non-consecutive dibasic amino acids and is cleaved by trypsin-like proteases located in the lung and intestinal tract of birds. This restricted HA maturation is responsible for mild or quasi-unapparent clinical signs depending on the viral strain and the host species. Nucleotide substitutions, insertions, and non-homologous recombination between the host (ribosomal RNA 28S) and viral genes (matrix and nucleoprotein segments) have been observed to be responsible for MBCS
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