Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.729936
Title: Investigating the mechanisms by which influenza A viruses induce and subsequently dampen the Type I interferon response
Author: Long, Joshua
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Abstract:
The activation of antiviral innate immune responses by influenza A viruses plays a keys role in influenza virus infections. The recognition of viral RNA by the pattern recognition receptor RIG-I leads to the induction of the expression of Type I Interferons, which induce an antiviral state, and to the activation of the inflammasome, which leads to inflammation. This thesis focuses on investigating both the mechanisms by which RIG-I is activated by influenza A viruses and the mechanisms by which influenza A viruses dampen the subsequent interferon response. In this thesis, I provide evidence to support the hypothesis that the depletion of free nucleoprotein within infected cells promotes the accumulation of immunostimulatory, internal deletion viral RNAs of approximately 50 to 75 nucleotides in length, and that these may be key in the activation of RIG-I. Furthermore, I provide preliminary evidence that the polymerases of avian adapted influenza virus strains may generate higher levels of these immunostimulatory RNAs, and speculate that this may be important in the innate immune over-activation and subsequent cytokine storm which occurs during human infections with a number of avian-adapted influenza A viruses. Furthermore, I investigate previous reports that the localisation of the PB2 subunit of the influenza virus trimeric polymerase to the mitochondria is important in dampening the expression of interferon by seeking to characterise the functions of mitochondrial localised PB2. I demonstrate that mitochondrial localising PB2 is imported into the matrix space and identify a number of matrixlocalising interactors of PB2. This work demonstrates that mitochondrial PB2 is not correctly localised to interact with the mitochondrial antiviral signalling protein MAVS, which was previously believed to be the manner by which PB2 dampens the induction of interferon expression. However, I speculate that the interaction of PB2 with the matrix protein translation elongation factor Tu may mediate its dampening activity.
Supervisor: Fodor, Ervin Sponsor: Medical Research Council ; University of Oxford
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.729936  DOI: Not available
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