Calcium dependent host innate immune resistance to influenza A virus infection

Goulding, Leah V. (2019) Calcium dependent host innate immune resistance to influenza A virus infection. PhD thesis, University of Nottingham.

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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.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chang, Kin-chow
Bennett, Malcolm
Keywords: Influenza A virus; Antiviral resistance; Store-operated calcium entry
Subjects: Q Science > QR Microbiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID: 56237
Depositing User: Goulding, Leah
Date Deposited: 19 Jul 2019 04:40
Last Modified: 07 May 2020 11:46
URI: http://eprints.nottingham.ac.uk/id/eprint/56237

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