Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780089
Title: Calcium dependent host innate immune resistance to influenza A virus infection
Author: Goulding, Leah V.
ISNI:       0000 0004 7965 7792
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2019
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Abstract:
Influenza A virus infection is a major threat to public health, claiming over half a million lives globally each year. Strategies to combat influenza virus infection include vaccination and antiviral therapy. Influenza virus vaccine escape mutants, arising from mutations resulting in antigenic alterations of their surface glycoproteins so they are no longer recognised by the host immune system, can limit the effectiveness of vaccines. Secondly, antivirals that directly target the virus inevitably apply selection pressure on the virus and lead to drug resistance. The onset of resistance has been documented for the neuraminidase inhibitors, currently the only class of anti-influenza drugs recommended by the World Health Organisation. Targeting host factors that are required by the pathogen or enhancing host immune responses has been identified as an alternative to direct antiviral therapy. Host targeted treatment could be a viable alternative to overcome the serious problem of antiviral resistance. The evidence presented here indicates that activation of a specific host Ca2+ mobilisation pathway, store-operated calcium entry (SOCE), mediates a potent antiviral innate immune response that dramatically inhibits influenza virus replication in a variety of cell types. Non-cytotoxic doses of an SOCE agonist, a sesquiterpene lactone thapsigargin (TG), induced a sustained and broad spectrum innate immune state which was effective against the virus pre- and post-infection. TG priming induced the endoplasmic reticulum stress unfolded protein response and enhanced type I/III IFN associated response in the face of infection. In addition, TG priming reduced the expression of a range proviral host factors required for post-translational viral protein transport and modification. In summary, the strategic pharmacological or genetic activation of SOCE could underpin a new host-centric therapeutic approach capable of effectively inhibiting influenza A virus replication. TG was identified as a potential broad spectrum inhibitor of RNA virus replication capable of activating multiple host innate immune responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.780089  DOI: Not available
Keywords: QR Microbiology
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