Literature detail

The C-terminus of non-structural protein 1 (NS1) in H5N8 clade 2.3.4.4 avian influenza virus affects virus fitness in human cells and virulence in mice.

Claudia Blaurock¹ Ulrike Blohm² Christine Luttermann² Julia Holzerland¹ David Scheibner¹ Alexander Schäfer² Allison Groseth¹ Thomas C Mettenleiter³ Elsayed M Abdelwhab¹

Affiliations 3 institutions

Institute of Molecular Virology and Cell Biology, Federal Research Institute for Animal Health Greifswald-Insel Riems, Germany.
Institute of Immunology, Federal Research Institute for Animal Health Greifswald-Insel Riems, Germany.
Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health Greifswald-Insel Riems, Germany.

PMID 34420477 2021 Emerg Microbes Infect eng ppublish

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Article

Publication summary

Avian influenza viruses (AIV) H5N8 clade 2.3.4.4 pose a public health threat but the viral factors relevant for its potential adaptation to mammals are largely unknown. The non-structural protein 1 (NS1) of influenza viruses is an essential interferon antagonist. It commonly consists of 230 amino acids, but variations in the disordered C-terminus resulted in truncation or extension of NS1 with a possible impact on virus fitness in mammals. Here, we analysed NS1 sequences from 1902 to 2020 representing human influenza viruses (hIAV) as well as AIV in birds, humans and other mammals and with an emphasis on the panzootic AIV subtype H5N8 clade 2.3.4.4A (H5N8-A) from 2013 to 2015 and clade 2.3.4.4B (H5N8-B) since 2016. We found a high degree of prevalence for short NS1 sequences among hIAV, zoonotic AIV and H5N8-B, while AIV and H5N8-A had longer NS1 sequences. We assessed the fitness of recombinant H5N8-A and H5N8-B viruses carrying NS1 proteins with different lengths in human cells and in mice. H5N8-B with a short NS1, similar to hIAV or AIV from a human or other mammal-origins, was more efficient at blocking apoptosis and interferon-induction without a significant impact on virus replication in human cells. In mice, shortening of the NS1 of H5N8-A increased virus virulence, while the extension of NS1 of H5N8-B reduced virus virulence and replication. Taken together, we have described the biological impact of variation in the NS1 C-terminus in hIAV and AIV and shown that this affects virus fitness <i>in vitro</i> and <i>in vivo</i>.

apoptosis Avian influenza virus H5N8 clade 2.3.4.4 interferon antagonism Interspecies Transmission mammals NS1 virulence Genetic Fitness A549 Cells Animals Cells, Cultured Chickens Dogs Ducks Female HEK293 Cells Humans

Structured evidence records

Evidence records

4 total

Host Range Experiment 2 records

Host Range Experiment Extraction confidence 0.90

Key finding

Recombinant H5N8 avian influenza viruses with modified NS1 lengths were experimentally tested and showed replication in human cells and altered virulence in mice.

Virus

Host

Location

Supporting text

We assessed the fitness of recombinant H5N8-A and H5N8-B viruses carrying NS1 proteins with different lengths in human cells and in mice.

Method: recombinant virus assay; replication assay
Experimental system: in vitro cell culture

Host Range Experiment Extraction confidence 0.90

Key finding

Infection experiments in mice showed that NS1 truncation increased H5N8 virulence whereas extension reduced virulence and replication.

Virus

Host

Location

Supporting text

In mice, shortening of the NS1 of H5N8-A increased virus virulence, while the extension of NS1 of H5N8-B reduced virus virulence and replication.

Method: experimental infection; virulence assay
Experimental system: in vivo animal experiment

Genomic Evolution 1 records

Genomic Evolution Extraction confidence 0.80

Key finding

NS1 sequence analysis showed that H5N8-B viruses and mammal-origin avian influenza viruses have shorter NS1 C-termini, whereas H5N8-A and bird influenza viruses have longer NS1 sequences, reflecting genomic variation linked to host adaptation.

Virus

Host

Location

Supporting text

Here, we analysed NS1 sequences from 1902 to 2020 representing human influenza viruses (hIAV) as well as AIV in birds, humans and other mammals and with an emphasis on the panzootic AIV subtype H5N8 clade 2.3.4.4A (H5N8-A) from 2013 to 2015 and clade 2.3.4.4B (H5N8-B) since 2016.

Genes or proteins: NS1
Analysis methods: sequence analysis

Molecular Adaptation 1 records

Molecular Adaptation Extraction confidence 0.95

Key finding

Shortening of the NS1 C-terminus in H5N8 avian influenza viruses enhances interferon antagonism and virulence in mammals, indicating adaptive molecular changes for mammalian hosts.

Virus

Host

Location

Supporting text

H5N8-B with a short NS1, similar to hIAV or AIV from a human or other mammal-origins, was more efficient at blocking apoptosis and interferon-induction without a significant impact on virus replication in human cells. In mice, shortening of the NS1 of H5N8-A increased virus virulence, while the extension of NS1 of H5N8-B reduced virus virulence and replication.

Genes or proteins: NS1
Mechanism types: interferon_antagonism; pathogenicity; replication_efficiency

Citation context

References

59 references

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Evidence overview

Evidence 4

Types 3

Virus 1

Host 5

Evidence types

Host Range Experiment 2 Genomic Evolution 1 Molecular Adaptation 1

Linked entities

Viruses

Hosts

Locations

Publication metadata

Journal: Emerging microbes & infections
Volume / Issue / Pages: 10 / 1 / 1760-1776
ISSN: 2222-1751
Journal country: United States
DOI: 10.1080/22221751.2021.1971568