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Innate antiviral defence depends on virus recognition and cytokines like interferon (IFN) that upregulate many interferon-stimulated genes (ISGs). Virus recognition normally relies on pattern recognition receptors binding to virus-associated nucleic acid motifs, but virus activity may provide an additional means for the cell to recognize infection. Enveloped viruses fuse with a cell membrane during entry and membrane fusion by virus-like particles or the purified protein p14 are sufficient to upregulate ISGs in the absence of viral nucleic acid. This thesis examines the mechanism by which cells recognize membrane fusion and how this affects downstream signalling and upregulation of ISGs. We found that membrane perturbation by enveloped virus particles or p14 triggered cytosolic Ca2+ oscillations important for antiviral defence. Surprisingly, Ca2+ signalling seemed to act upstream of nucleic acid sensing pathways during enveloped virus infection. In the absence of viral nucleic acid, p14 triggered a Ca2+-dependent antiviral response to dsRNA. It is still unclear how p14 might trigger recognition of endogenous dsRNA. We found that enveloped virus particles trigger IRF3-mediated upregulation of interferon as well as direct IFN-independent upregulation of ISGs. Furthermore, while some viruses like HCMV trigger widespread IRF3 activation, other viruses like SeV upregulate IRF3 and IFN in a minority of infected cells. This disparate response to infection can lead to different biological outcomes when measured at the population level. Our work highlights the complexity of the response to enveloped virus particles, despite the absence of replication. Further work is necessary to understand how membrane perturbation is recognized and how this interfaces with nucleic acid sensing. While nucleic acid sensing is sufficient to upregulate antiviral ISGs, other signals like membrane perturbation may provide important contextual cues during infection. This will be important to understand moving forward as virus-like particles are used more and more for research and clinical applications. / Thesis / Doctor of Philosophy (PhD) / Cells rely on pattern recognition receptors for innate antiviral defence. While the study of pattern recognition has focused on virus-associated nucleic acid motifs, disruptions of the cellular environment during virus infection could similarly warn the cell. Membrane perturbation during enveloped virus entry is associated with upregulation of antiviral interferon-stimulated genes. This thesis examines the mechanism of membrane perturbation sensing and different antiviral signalling pathways activated by non-replicating enveloped virus particles. We found evidence that membrane perturbation triggers cytosolic Ca2+ signalling which may act as a co-stimulatory signal for recognition of incoming viral nucleic acid. We initially thought enveloped virus particles were recognized through a common pathway, but have since learned that recognition is more complex. Further work is necessary to understand how membrane perturbation and nucleic acid sensing interface during enveloped virus infection and what role this plays in antiviral defence.