Type I interferons (IFN) are a potent antiviral cytokine group that are key regulators of the immune response against virus infection. Not only does this group activate antiviral states within target cells, it can modulate the innate immune response. In the studies presented, we investigate the effects of type I IFN on the innate immune system during a mucosal vaginal virus infection, herpes simplex virus type 2 (HSV-2), a prominent sexually transmitted infection that causes genital herpes and increases risk of human immunodeficiency virus acquisition. It is well known that type I IFN is critical for natural killer (NK) cell activation. These cells contribute to the antiviral response by suppressing virus replication and aiding in the initiation of the adaptive immune response, particularly through the release of IFN-γ. In the work presented, we demonstrate that type I IFN does not act on NK cells directly for their activation, but instead activates NK cell IFN-γ production by inducing inflammatory monocytes to release IL-18, which in turn, signals NK cells to release IFN-γ during a mucosal HSV-2 infection. Rather, direct action of type I IFN on NK cells serves to negatively regulate their IFN-γ response. We also found that type I IFN was critical for suppressing virus-induced innate immunopathology during HSV-2 infection. Overall, our studies further our understanding of type I IFN and the many roles it plays during virus infection, which has become more relevant as specific therapies altering type I IFN are being used in the clinic. Further, we provide a fundamental understanding of type I IFN and its ability to shape the innate immune response to virus infection by suppressing dysregulated and immunopathological functions while promoting beneficial innate immune responses that can help fight the infection. / Thesis / Doctor of Philosophy (PhD) / Type I interferons (IFN) are a group of proteins that are rapidly produced early during infection and is important for combatting virus infections. We show that type I IFN is not just an antiviral molecule, but can modulate the initial immune response to virus infection. As part of the initial immune response, Natural killer (NK) cells are immune cells that respond rapidly to infection and are a key element in controlling the early stages of infection. We found that type I IFN is critical for activating NK cell function by signaling through an intermediary cell, but can also suppress that same function by directly acting on NK cells. We also found that type I IFN is critical for suppressing a dysregulated immune response that causes severe virus-induced vaginal pathology. Overall, our data suggests that type I IFN is a key antiviral molecule that shapes the immune response to virus infection.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22029 |
| Date | January 2017 |
| Creators | Lee, Amanda |
| Contributors | Ashkar, Ali, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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