dc.contributor.advisor | Digard, Paul | en |
dc.contributor.advisor | Dutia, Bernadette | en |
dc.contributor.author | Turnbull, Matthew Luke | en |
dc.date.accessioned | 2017-11-09T11:25:32Z | |
dc.date.available | 2017-11-09T11:25:32Z | |
dc.date.issued | 2017-07-08 | |
dc.identifier.uri | http://hdl.handle.net/1842/25468 | |
dc.description.abstract | Influenza A virus (IAV) circulates in waterfowl, causing mostly asymptomatic
infections. IAV can undergo host adaptation and evolve to cause significant disease
and mortality in domestic poultry and mammals, applying an enormous socio-economic
burden on society. Sporadically, IAV causes global pandemics in man due
to its zoonotic nature, and this can result in millions of deaths worldwide during a
single outbreak. Host adaptation of IAV is an incompletely understood phenomenon,
but is known to involve both host and viral determinants. It is essential to improve the
understanding of the factors governing host range and pathogenicity of avian IAV,
especially given the absence of a universal influenza vaccine and a limited weaponry
of effective antiviral compounds. This study set out to improve the understanding of
host adaptation of avian IAV, focussing on segment 8 (NS segment) of the virus
genome.
The NS segment of non-chiropteran IAV circulates as two phylogenetically
distinct clades – the ‘A-’ and ‘B-alleles’. The A-allele is found in avian and
mammalian viruses, but the B-allele is considered to be almost exclusively avian. This
might result from one or both of the major NS gene products (NS1 and NEP) being
non-functional in mammalian host cells, or from an inability of segment 8 RNA to
package into mammalian-adapted strains. To investigate this, the NS segments from a
panel of avian A- and B-allele strains were introduced into human H1N1 and H3N2
viruses by reverse genetics. A- and B-allele reassortant viruses replicated equally well
in a variety of mammalian cell types in vitro. Surprisingly, the consensus B-allele
segment 8 out-competed an A-allele counterpart when reassortant H1N1 viruses were
co-infected, with the parental WT segment 8 being most fit in this system. A- and B-allele NS1 proteins were equally efficient at blocking the mammalian IFN response
both in the context of viral infection and in transfection-based reporter assays.
Consensus A- and B-allele H1N1 viruses also caused disease in mice and replicated to
high virus titre in the lung. Interestingly, the B-allele virus induced more weight-loss
than the A-allele, although the parental WT virus was most pathogenic in vivo.
To re-address the hypothesis that B-allele NS genes really are avian-restricted,
the relative rates of independent Aves to Mammalia incursion events of A- and B-allele
lineage IAV strains was estimated and compared using phylogenetic analyses of all
publically available segment 8 sequences. 32 A-allele introduction events were
estimated compared to 6 B-allele incursions, however the total number of avian Aallele
sequences outnumbered B-allele sequences by over 3.5 to 1, and the relative
rates of introduction were not significantly different across the two lineages suggesting
no bias against avian B-allele NS segments entering mammalian hosts in nature.
Therefore, this study provides evidence that avian B-allele NS genes are not
attenuating in mammalian hosts and are able to cause severe disease. Thus, this lineage
of IAV genes, previously assumed to be avian-restricted, should be considered when
assessing zoonotic potential and pandemic risk of circulating avian IAVs. | en |
dc.contributor.sponsor | Biotechnology and Biological Sciences Research Council (BBSRC) | en |
dc.language.iso | en | |
dc.publisher | The University of Edinburgh | en |
dc.relation.hasversion | Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity (Turnbull ML, Wise HM, Nicol MQ, Smith N, Dunfee RL, Beard PM, Jagger BW, Ligertwood Y, Hardisty GR, Xiao H, Benton DJ, Coburn AM, Paulo JA, Gygi SP, McCauley JW, Taubenberger JK, Lycett SJ, Weekes MP, Dutia BM, Digard P). 2016. Journal of Virology. 90, 9263-84. DOI: 10.1128/JVI.01205-16. | en |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | |
dc.subject | influenza A virus | en |
dc.subject | host range | en |
dc.subject | pathogenicity | en |
dc.subject | nonstructural | en |
dc.subject | allele | en |
dc.subject | B-allele | en |
dc.title | Role of the NS segment of Influenza A virus in setting host range and pathogenicity | en |
dc.type | Thesis or Dissertation | en |
dc.type.qualificationlevel | Doctoral | en |
dc.type.qualificationname | PhD Doctor of Philosophy | en |