Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656706
Title: The cellular and molecular basis of transmission of influenza viruses
Author: Blumenkrantz, Deena
ISNI:       0000 0004 5349 178X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Abstract:
Pandemic influenza viruses are responsible for many deaths and much suffering as well as large costs accumulated through healthcare provision and lost productivity. The swine-origin H1N1 influenza virus that was at the root of the pandemic in 2009, although considered mild, in the UK alone caused the deaths of 361 people, subjected 1,700 to critical care and led to hospital admission of 7,879, before summer 2010. This virus is now embedded in the human population and will remain there, inducing further mortality, morbidity, and cost until it is replaced by a new pandemic influenza virus and the cycle repeats. However, if we improve our understanding of the characteristics of virus/host interactions that support transmission, we may be able to identify potentially problematic strains, improve our preparedness and ultimately prevent future pandemics. The ability of an influenza virus to transmit from host to host is multifactorial. One role proven to be important because its inhibition by drugs prevents replication is the ability of neuraminidase (NA) to cleave sialic acid (SA). NAs of recently circulating influenza viruses were analysed with the aim of identifying characteristics that might support new or previous pandemic influenza virus strains. NA stalk truncation, induced by influenza virus transmission through gallinaceous poultry, was found to hinder transmission through the air of an otherwise transmissible virus. While this genetic ablation did not directly affect sialidase activity, when measured using a small soluble substrate, it did reduce the ability of virions to release complex tethered substrates, separate from one another and penetrate through mucus. This work suggests that the next pandemic virus is unlikely to have a short stalk NA. Previously, loss of the ability of NA to haemabsorb (Hb) chicken red blood cells (CRBSs) was associated with the adaptation of an influenza virus from avian to human hosts and a single amino acid mutation was shown to reinstate the haemabsorption ability of an NA from a prototypic pandemic H2N2 virus of avian-origin. This thesis shows that the human-adapted 2009 pandemic N1 NA, which arose from the introduction of an avian influenza virus into swine, did not Hb CRBCs, as expected. However, unexpectedly, many back mutations to make the 2009 N1 resemble an NA that did Hb also did not alter this characteristic. Further investigations showed that some NAs from both avian and swine influenza viruses also did not Hb, despite the fact that NA haemabsorption increased viral growth in airway culture cells. Thus we conclude that loss of Hb occurs within birds, before a virus can cross the species barrier into mammals and this may be due to a reduction, rather than a gain, in activity.
Supervisor: Barclay, Wendy Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.656706  DOI: Not available
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