Upon infection with a virus, a cellular innate immune response is rapidly initiated to contain the pathogen. A potent interferon (IFN)-α/β cytokine response underlies host defence by prompting the expression of antiviral genes and stimulating adaptive immunity. Pattern recognition receptors (PRRs) are integral components of this response, as they recognize molecules specific to pathogens, including viral nucleic acids and couple to IFN induction. For my studies, I pursued lines of investigation aimed at deepening our understanding of immune responses trigered by the sensing of viruses within the cell cytosol. Initially, I focused on the PRR RIG-I. This RNA helicase senses RNA present in the cytosol of mammalian cells infected with certain negative-sense RNA viruses. Although many molecules capable of activating RIG-I had been proposed, the precise nature and contribution of RIG-I agonists during the course of a viral infection was undefined. I was able to show with the help of two colleagues that viral genomic RNA, but not other RNA species, constitutes the prominent source for RIG-I activation in influenza and Sendai virus infected cells. Next, I focused on the identification of new regulators of the innate pathways dedicated to the sensing of cytosolic nucleic acids following infection. My first approach, involving the use of a vaccinia-encoded immunomodulator as bait for novel components of the cytosolic DNA sensing pathway, was unsuccessful. So I turned my attention to DDX60: an IFN-inducible superkiller-2- like RNA helicase that I fished-out from microarray data. I was able to generate a ddx60-knockout mouse and demonstrate that this helicase is dispensable for the induction of IFN-α/β in response to different PRR stimuli. These results shed light on the role of this poorly characterized helicase in antiviral immunity and suggest that DDX60 may function as a specific antiviral restriction factor rather than a component of the IFN-inducing PRR pathways.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625980 |
| Date | January 2012 |
| Creators | Goubau, D. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1381930/ |
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