Highly Pathogenic Avian Influenza H5N1 Virus Infections in Wild Red Foxes (Vulpes vulpes) Show Neurotropism and Adaptive Virus Mutations

Bordes, Luca; Vreman, Sandra; Heutink, René; Roose, Marit; Venema, Sandra; Pritz‐Verschuren, Sylvia B. E.; Rijks, Jolianne M.; Gonzáles, José L.; Germeraad, Evelien A.; Engelsma, Marc; Beerens, Nancy

doi:10.1128/spectrum.02867-22

Cited by 59 publications

(73 citation statements)

References 30 publications

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“…We also identified an additional 30 sites spread across all genomic segments (Figure 4, Supplementary Table 2), including 4 in PB2 (I463V, L464M, V478I, I616V), 5 in PB1 (T59S, E264D, L378M, G399D, K429R), 11 in PBP1-F2 (T7I, S12L, N17S, R21K, Y42C, P48Q, Q54R, I55T, Y57S, W58L, G70E), 1 in PA (M441V), 2 in HA (I511V, V533M), 1 in NP (F230L), 2 in NA (L269M, S339P), 2 in M1 (N87T, A200V), 1 in M2 (R61G) and 2 in NS1 (C111S, G166D). We did not find mutations in PB2 (E627K, D701N, K702R) that have been specifically linked to mammalian host adaptation and enhanced transmission 24,26 . We also did not find mutations specific to mammalian or bird strains that might support mammalian host adaptation, but we did find a small number of isolated mutations in single birds (not shown) or mammals (Supplement table 2).…”

Section: Resultscontrasting

confidence: 62%

Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru

Leguía

Garcia-Glaessner

Muñoz-Saavedra

et al. 2023

Preprint

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Highly pathogenic avian influenza (HPAI) A/H5N1 viruses (lineage 2.3.4.4b) are rapidly invading the Americas, threatening wildlife, poultry, and potentially evolving into the next global pandemic. In November 2022, HPAI arrived in Peru, where massive pelican and sea lion die-offs are still underway. We report complete genomic characterization of HPAI/H5N1 viruses in five species of marine mammals and seabirds (dolphins, sea lions, sanderlings, pelicans and cormorants) sampled since November 2022. All Peruvian viruses belong to the HPAI A/H5N1 lineage 2.3.4.4b, but they are 4:4 reassortants where 4 genomic segments (PA, HA, NA and MP) position within the Eurasian lineage that initially entered North America from Eurasia, while the other 4 genomic segments (PB2, PB1, NP and NS) position within the American lineage (clade C) that was already circulating in North America. These viruses are rapidly accruing mutations as they spread south. Peruvian viruses do not contain PB2 E627K or D701N mutations linked to mammalian host adaptation and enhanced transmission, but at least 8 novel polymorphic sites warrant further examination. This is the first report of HPAI A/H5N1 in marine birds and mammals from South America, highlighting an urgent need for active local surveillance to manage outbreaks and limit spillover into humans.

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Section: Resultscontrasting

confidence: 62%

Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru

Leguía

Garcia-Glaessner

Muñoz-Saavedra

et al. 2023

Preprint

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“…RT.Hawk/ON/22 and Redfox/ON/22 infected animals succumbed to infection within one week, indicating higher virulence. One RT.Hawk/ON/22 and both Redfox/ON/22 animals showed detectable infectious virus in the brain, consistent with reports of neurotropism of H5N1 in infected foxes 27 . The molecular determinants of the higher degree of pathogenicity seen in our experiment with each of the four viruses are unknown; however, future studies to determine the role of some of the newly reassorted North American gene segments and some of the unique amino acid residues are warranted.…”

Section: Discussionsupporting

confidence: 88%

“…Most animals had high levels of infectious virus in either respiratory tissues, and sporadically in systemic organs including the liver, kidney, spleen, and/or the brain, showing systemic spread following intranasal infection. Half of the infected animals that had brains collected at the time of euthanasia, as well as one contact animal, had detectable infectious virus in the brain, confirming neurotropism, consistent with a previous report of infection in foxes 27 . One animal infected with each of BWTE/MB/22 and Redfox/PEI/22 had no detectable virus in any tissues tested.…”

Section: Hpai (H5n1) Transmission In Ferretssupporting

confidence: 89%

Transmission of lethal H5N1 clade 2.3.4.4b avian influenza in ferrets

Kobasa

Warner

Alkie

et al. 2023

Preprint

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Highly pathogenic avian influenza viruses of the H5N1 subtype are highly lethal in many avian species. Since 2014, viruses of the genetically distinct clade 2.3.4.4 have been circulating in Eurasia, Africa and briefly in North America, killing millions of wild and domestic birds. In December, 2021 clade 2.3.4.4b H5N1 viruses were first isolated from poultry and wild birds in Canada. Further spread of H5N1 viruses has since led to infection in many terrestrial and aquatic mammalian species. Some of the H5N1 viruses isolated from mammals have acquired adaptations previously shown to increase viral replication in mammals as well as novel patterns of reassortment of internal gene segments with North American (NA) lineage influenza A viruses (IAVs). While there have been few human cases of infection with clade 2.3.4.4b viruses reported to date, the potential for spillover, particularly of viruses harboring mammalian adaptation signatures remains a critical concern. Here we show that multiple naturally circulating reassortant H5N1 viruses can replicate in primary human airway epithelial cells and cause lethal disease in multiple mammalian species. One isolate, A/Red Tailed Hawk/ON/FAV-0473-4/2022, efficiently transmitted by direct contact between ferrets, resulting in lethal outcomes. Historically, H5 subtype viruses do not transmit effectively between mammals, and recent studies of currently circulating H5N1 viruses showed mild infection outcome in ferrets without detectable transmission. While known specific mutations within the Eurasian lineage H5Nx viruses have allowed for increased viral fitness in mammals, reassortment of H5N1 viruses with NA lineage avian IAVs may be unpredictably (unexpectedly) contributing to further enhancements in virulence and transmissibility in mammals, with potential increased risk to humans. Our research has determined that certain, as yet uncharacterized, genetic signatures may be important determinants of mammalian adaptation and pathogenicity of these viruses. Ongoing surveillance of circulating HPAI A(H5N1) viruses across species, including humans, should be a top priority so as to promptly identify viruses that may have pandemic or outbreak potential in mammals.

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“…One of the most worrying issues of the current panzootic is the increasing cases of H5N1 infections in wild mammals, both marine and terrestrial, causing unprecedented mass mortalities (Ramey et al 2022, Bordes et al 2023, Gamarra-Toledo et al 2023b, Leguia et al 2023, Puryear et al 2023. Worryingly, RNA sequencing has shown signs of early adaptation of the H5N1 2.3.4.4b clade virus to wild mammals (Vreman et al 2023) and humans (Centers for Disease Control and Prevention 2023), fueling the fears of a new human pandemic (Kupferschmidt 2023).…”

Section: Discussionmentioning

confidence: 99%

“…This novel H5N1 virus has spread rapidly through major avian migratory pathways to every continent except Australia and Antarctica so far (Caliendo et al 2021, Bevins et al 2022, Shi et al 2023. Although it has major impacts on wild and domestic birds, the unusually high and growing number of lethal cases among marine and terrestrial mammals, especially in Europe and the Americas, are a hallmark of the current emergency (Bordes et al 2023, Gamarra-Toledo et al 2023b, Puryear et al 2023. Unprecedented mammal-to-mammal transmission has been increasingly suspected.…”

Section: Introductionmentioning

confidence: 99%

Spatio-temporal dynamics and drivers of Highly Pathogenic Avian Influenza H5N1 in Chile

Soto‐Azat

Alvarado‐Rybak²,

Aguilera

et al. 2023

Preprint

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Highly pathogenic avian influenza A H5N1 clade 2.3.4.4b (hereafter H5N1) is causing vast impacts on biodiversity and poultry around the globe. In Chile it was first reported on December 7th, 2022, in a pelican (Pelecanus thagus) found dead in the northern city of Arica. In the following months, lethal H5N1 cases were reported in a wide range of wild bird species, marine mammals, backyard and industrial poultry, and in a human. Despite its high impact and spread, it is not well-known what environmental factors are associated with outbreaks. This study describes the spatio-temporal patterns of the current epizootic of H5N1 in Chile and test ecological and anthropogenic drivers that could be associated with outbreak occurrence. We used H5N1 cases reported by the Chilean national animal health authority to the World Animal Health Information System (WAHIS) from December 9th, 2022, to March 3rd, 2023. These included bird cases confirmed through avian influenza specific real-time PCR assay (qPCR), obtained from passive and active surveillance. Data was analyzed to detect the presence of H5N1 clusters under space-time permutation probability modelling, H5N1 association between distance and days since first outbreak through linear regression, and correlation between H5N1 presence with a range of ecological and anthropogenic variables by general linear modelling. From the 197 H5N1 identified outbreaks, involving 478 individual cases among wild and domestic birds, a wave-like steady spread of H5N1 from north to south was identified, that can help predict hotspots of outbreak risk and establish targeted preventive measures. For instance, 14 statistically significant clusters were identified, with the largest located in central Chile (18-29 km in radius) where poultry production is concentrated. Also, one of the clusters was identified in Tocopilla, location where the H5N1 human case occurred time later. In addition, the presence of H5N1 outbreaks was positively correlated with bird richness, human footprint, precipitation of the wettest month, minimum temperature of the coldest month, and mean diurnal temperature. In contrast, presence of H5N1 was negatively correlated to distance to the closest urban center, precipitation seasonality and isothermality. Preventive actions based on our modeling approach include developing wildlife surveillance diagnostic capabilities in Chilean regions concentrating outbreaks. It is urgent that scientists, the poultry sector, local communities and national health authorities co-design and implement science-based measures from a One Health perspective to avoid further H5N1 spillover from wildlife to domestic animals and humans, including rapid removal and proper disposal of wild dead animals, and the closure of public areas (i.e., beaches) reporting high wildlife mortalities.

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Highly Pathogenic Avian Influenza H5N1 Virus Infections in Wild Red Foxes (Vulpes vulpes) Show Neurotropism and Adaptive Virus Mutations

Abstract: Highly pathogenic avian influenza (HPAI) viruses caused high mortality among wild birds from 2021 to 2022 in the Netherlands. Recently, three wild foxes were found to be infected with HPAI H5N1 viruses, likely due to the foxes feeding on infected birds.

Cited by 59 publications

References 30 publications

Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru

Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru

Transmission of lethal H5N1 clade 2.3.4.4b avian influenza in ferrets

Spatio-temporal dynamics and drivers of Highly Pathogenic Avian Influenza H5N1 in Chile

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