Abstract
BackgroundA characteristic difference between highly and non-highly pathogenic avian influenza strains is the presence of an extended, often multibasic, cleavage motif insertion in the hemagglutinin protein. Such motif is found in H7N3 strains from chicken farm outbreaks in 2012 in Mexico.MethodsThrough phylogenetic, sequence and structural analysis, we try to shed light on the role, prevalence, likelihood of appearance and origin of the inserted cleavage motifs in these H7N3 avian influenza strains.ResultsThe H7N3 avian influenza strain which caused outbreaks in chicken farms in June/July 2012 in Mexico has a new extended cleavage site which is the likely reason for its high pathogenicity in these birds. This cleavage site appears to have been naturally acquired and was not present in the closest low pathogenic precursors. Structural modeling shows that insertion of a productive cleavage site is quite flexible to accept insertions of different length and with sequences from different possible origins. Different from recent cleavage site insertions, the origin of the insert here is not from the viral genome but from host 28S ribosomal RNA (rRNA) instead. This is a novelty for a natural acquisition as a similar insertion has so far only been observed in a laboratory strain before. Given the abundance of viral and host RNA in infected cells, the acquisition of a pathogenicity-enhancing extended cleavage site through a similar route by other low-pathogenic avian strains in future does not seem unlikely. Important for surveillance of these H7N3 strains, the structural sites known to enhance mammalian airborne transmission are dominated by the characteristic avian residues and the risk of human to human transmission should currently be low but should be monitored for future changes accordingly.ConclusionsThis highly pathogenic H7N3 avian influenza strain acquired a novel extended cleavage site which likely originated from recombination with 28S rRNA from the avian host. Notably, this new virus can infect humans but currently lacks critical host receptor adaptations that would facilitate human to human transmission.
Highlights
A characteristic difference between highly and non-highly pathogenic avian influenza strains is the presence of an extended, often multibasic, cleavage motif insertion in the hemagglutinin protein
First, we investigated the frequency of extended cleavage site motifs of H7N3 strains in the EpiFlu database of the Global Initiative on Sharing All Influenza Data (GISAID) since the year 2000 (Figure 1)
It can be seen that most H7N3 strains collected from 2006 to 2011 lack extended cleavage motifs with the consensus R-x-x-R, while in 2012 in the Mexican chicken farm outbreak sequences, we do see a prominent reappearance of such a motif
Summary
A characteristic difference between highly and non-highly pathogenic avian influenza strains is the presence of an extended, often multibasic, cleavage motif insertion in the hemagglutinin protein. Such motif is found in H7N3 strains from chicken farm outbreaks in 2012 in Mexico. In some HPAI strains, in place of an MBCS, observations have been made of an extended cleavage site with multiple basic residues at positions other than the canonical site, which usually conform to the minimal R-x-x-R cleavage motif. We used phylogenetic, sequence and structural analysis to shed light on the origin of the extended cleavage motif in this H7N3 avian influenza strain from recombination with host 28S rRNA as well as evaluate its potential for human-to-human transmission
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