INVESTIGATING THE IMMUNOREGULATORY FUNCTIONS OF INTERFERONS DURING MUCOSAL VIRAL INFECTION
| dc.contributor.advisor | Ashkar, Emily | |
| dc.contributor.author | Feng, Emily | |
| dc.contributor.department | Medical Sciences (Molecular Virology and Immunology Program) | en_US |
| dc.date.accessioned | 2025-08-29T17:54:29Z | |
| dc.date.available | 2025-08-29T17:54:29Z | |
| dc.date.issued | 2025 | |
| dc.description.abstract | Inflammation during viral infections must be tightly regulated. While insufficient inflammation can impair viral clearance, excessive inflammation can cause irreparable tissue damage and impair host fitness. Interferons (IFNs), including type I, II, and III IFNs, are a family of cytokines central to the body’s antiviral defence. While IFNs are well-established for their ability to induce antiviral signalling to prevent viral replication and eliminate virally infected cells, their role in regulating antiviral immune responses is poorly understood. To investigate the immunoregulatory functions of IFNs during mucosal viral infections, we employed a mouse model of herpes simplex virus type 2 (HSV-2) in the female reproductive tract (FRT). We demonstrate that type I IFN signalling is critical to prevent hyperinflammation and immune-mediated pathology. In type I IFN-deficient mice (Ifnar-/-), HSV-2 infection leads to severe tissue pathology due to uncontrolled IL-6 production, which stimulates macrophage production of matrix metalloproteinases (MMPs) that degrade the extracellular matrix and compromise tissue integrity. We further find that IFN-γ, a type II IFN produced by natural killer (NK) cells, can also inhibit the development of immunopathology by directly antagonizing IL-6 signalling in macrophages. Finally, we identify that type III IFNs, also known as IFN-λ, are pleiotropic cytokines with potent immunoregulatory functions. Mucosal administration of IFN-λ in Ifnar-/- mice suppresses IL-6-driven pathology. Additionally, we found that IFN-λ treatment rescues deficits in the CD4+ T cell response observed in Ifnar-/- mice, thereby preventing viral dissemination and promoting viral clearance. Together, these findings highlight the complementary immunoregulatory roles of type I, II, and III IFNs during mucosal viral infections. Additionally, we provide a mechanistic insight into how IFNs can be harnessed therapeutically to limit pathogenic inflammation and enhance protective immunity. | en_US |
| dc.description.degree | Doctor of Philosophy (Medical Science) | en_US |
| dc.description.degreetype | Thesis | en_US |
| dc.description.layabstract | Inflammation during viral infection is a double-edged sword. Insufficient inflammation impairs the immune system’s ability to clear the virus, but excessive inflammation can cause collateral damage to tissues and organs. To develop new therapies that can restore balance in our immune response, we must deepen our understanding of the mechanisms that regulate inflammation. Interferons (IFN) – a class of cytokines that includes type I, II, and III IFNs – are well-known for their ability to block viral infection. They also play a key role in modulating immune responses. We find that this immune regulation involves not only promoting the development of protective immune responses, but also preventing the development of excessive, harmful immune responses. These interferons work together to provide broad antiviral effects and effective immune regulation to limit the pathogenic effects of viruses and the immune response. These discoveries reveal novel insights into how interferons coordinate the immune response and suggest potential therapeutic applications for severe viral infection. | en_US |
| dc.identifier.uri | http://hdl.handle.net/11375/32268 | |
| dc.language.iso | en | en_US |
| dc.title | INVESTIGATING THE IMMUNOREGULATORY FUNCTIONS OF INTERFERONS DURING MUCOSAL VIRAL INFECTION | en_US |
| dc.type | Thesis | en_US |