Evolutionary and temporal dynamics of emerging influenza D virus in Europe (2009–22)

Abstract

Influenza D virus (IDV) is an emerging influenza virus that was isolated for the first time in 2011 in the United States from swine with respiratory illness. Since then, IDV has been detected worldwide in different animal species and it was also reported in humans. Molecular epidemiological studies revealed the circulation of two major clades, named D/OK and D/660. Additional divergent clades have been described but have been limited to specific geographic areas (i.e. Japan, California). In Europe, IDV was detected for the first time in France in 2012 and subsequently also in Italy, Luxembourg, Ireland, UK, Switzerland and Denmark. To understand the time of introduction and the evolutionary dynamics of IDV on the continent, molecular screening of bovine and swine clinical samples was carried out in different European countries and phylogenetic analyses were performed on all available and newly generated sequences. Until recently, D/OK was the only clade detected in this area. Starting from 2019, an increase of D/660 clade detections was observed, accompanied by an increase in the overall viral genetic diversity and genetic reassortments. The time to the most recent common ancestor (tMRCA) of all existing IDV sequences was estimated as 1995 – 16 years before its discovery, indicating that the virus could have started its global spread in this timeframe. Despite D/OK and D/660 clades having a similar mean tMRCA (2007), the mean tMRCA for European D/OK sequences was estimated as January 2013 compared to July 2014 for European D/660 sequences. This indicated that the two clades were likely introduced on the European continent at different time points, as confirmed by virological screening findings. The mean nucleotide substitution rate of the Hemagglutinin-Esterase-Fusion (HEF) glycoprotein segment was estimated as 1.403 x 10¯³ substitutions/site/year, which is significantly higher than the one of the HEF of human Influenza C virus (p<0.0001). IDV genetic drift, the introduction of new clades on the continent and multiple reassortment patterns shape the increasing viral diversity observed in the last years. Its elevated substitution rate, diffusion in various animal species and the growing evidence pointing towards zoonotic potential justify continuous surveillance of this emerging Influenza virus.

Developing an integrated approach to assess the emergence threat associated with influenza D viruses’ circulating in Europe

“…Our first partnering project generated a comparison of IDV seroprevalences in livestock of different EU countries (Gaudino et al, 2021) and showed that live cattle import countries harbour higher IDV seroprevalences than export countries, suggesting infection at trade age and/or facilitated by transportation stress and animals mixing. Genetic characterisation of IDV strains also highlighted the co-circulation of mainly two clades of IDV-namely D/OK and D/660that were introduced in Europe around early 2013 and mid 2014 respectively (Gaudino et al, 2022). From there, IDV spread through the continent, as shown by detections in France, Italy, Ireland, Luxembourg, and Sweden (Chiapponi et al, 2016;Chiapponi et al, 2019;Foni et al, 2017;) as well as other EU countries outside this consortium.…”

IDV Typer: An Automated Tool for Lineage Typing of Influenza D Viruses Based on Return Time Distribution

“…The lineages D/Yama2016, D/Yama2019 and D/CA2019 included five, five and three members, respectively, hence two sequences each from D/Yama2016, D/Yama2019 and D/CA2019 were included in the reference dataset. The D/France2012 lineage (tentative sixth lineage) included in reference dataset consisted of a single entry D/bovine/France/2986/2012 (Accession ID: LN559126) as it forms an independent branch outside the other known lineages [ 49 , 50 ]. Thus, a reference dataset of 23 entries was used as a training dataset for optimization of k and designing of RTD-based lineage typing method for IDV.…”

“…The sequences used in the reference dataset were excluded from the list of significant hits, and thus a total of 143 entries were obtained. The lineage information for 142/143 entries was compiled from the literature review [ 11 , 12 , 15 , 17 , 18 , 36 , 45 , 46 , 50 , 61 ].…”

“…An IDV isolate similar to swine and bovine IDV in the US was sequenced in France in 2012 [ 6 ] and reported to form a separate cluster from the clusters of known lineages. This isolate was annotated as lineage D/Fra [ 49 ] or D/France-2012 [ 50 ] by different groups.…”

Zoonotic Animal Influenza Virus and Potential Mixing Vessel Hosts

“…IDV was detected in pigs in the USA in 2011, although cattle are the primary reservoir [173]. In addition to North America, IDV has been isolated in Europe, Asia, Africa, and South America [174,175]. IDV has the ability to expand its mammalian-host spectrum to small ruminants (sheep, goats), horses, and camelids under natural conditions, and infects mice, ferrets, and guinea pigs under experimental conditions [176].…”