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The first risk assessment tool to predict the emergence of high pathogenicity H5/H7 Avian Influenza variants
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International audience. Avian Influenza viruses can be distinguished in two groups, low pathogenicity avian influenza viruses (LPAIV), and high pathogenicity avian influenza viruses (HPAIV). While LPAIV cause only mild symptoms and a low lethality in poultry, HPAIV causes a systemic infection with high lethality rates and an extended tropism with zoonotic potential [1]. LPAIV can sometimes switch into HPAIV by an insertion of several basic amino acids in the cleavage site of the hemagglutinin protein (HA). The presence of these novel amino acids creates a multibasic cleavage site (MBCS) that changes the tropism of the virus and allows systemic dissemination. Although this transition has been documented, the associated mechanism remained unclear, with only some traceable insights such as small indels, substitutions and recombination events [2]. We experimentally identified the mechanism that guides insertion driven HPAIV emergence, using 18 different HA viral templates, combined with ultra-high-fidelity sequencing and bioinformatic modelling of polymerase backtrack events. Using these results, we created an algorithm capable of estimating the INDEL accumulation potential of a complete HA5 sequence, identify the insertion hotspots and predict the frequency and identity of potential insertions. This novel piece of software allowed us a complete exploration of all the known diversity of H5 HA sequences that comprises more than 900 unique sequences, that we found, have different levels of INDEL accumulation depending on the primary nucleotide sequence.We explored the functional implications of these INDELS, recreating the potential MBCS that could emerge and the alternative evolutive pathways they can induce in the virus. We also identified two possible pathways of emergence for HPAIV, one implies an immediate transition of the LPAIV variant while the second implies an accumulation of frameshift insertions that eventually will pileup 3 or multiple of 3 nucleotides, and hence recover protein function with extra amino acids. The final objective is to create an automated online tool and app capable of classify all the H5 existing viruses depending on their backtrack potential, their most-likely evolutive pathway and potential MBCS composition, providing the first risk assessment tool for LPAIV-HPAIV transition.
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