부산대학교 도서관

Appropriate host immune responses to acute viral respiratory infections are necessary for viral clearance and can determine clinical disease severity. Two such respiratory infections are coronavirus disease-19 (COVID-19) and influenza, the causative agents of which are severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV), respectively. Interferon (IFN)-induced transmembrane protein 3 (IFITM3), an innate immune effector, has been shown to restrict replication of IAVs and several other enveloped RNA viruses. While, both anti- and pro-viral activities of IFITM3 have been reported for SARS-CoV-2. Understanding the role of IFITM3 during virus infection is vital as it presents an opportunity to increase viral restriction, but it has yet to be fully elucidated and appears to change subject to the virus. At later stages of an infection, T cells are essential in viral immunity. While T cell responses to IAVs are well characterised, responses against SARS-CoV-2 were poorly defined when the COVID-19 started to spread worldwide in early 2020. The first part of this study (Chapter 3) investigates the impact of IFITM3 during IAV and SARS-CoV-2 infection using induced pluripotent stem cell (iPSC)-derived macrophages (iPSDMs). Our data demonstrated IFITM3 as a restrictor for H1N1 infection, a subtype of IAV, while a facilitator for SARS-CoV-2 in iPSDMs. By analysing RNA-Seq data from IFITM3+/+ and IFITM3-/- iPSDMs following virus infection, we uncovered potential associations of IFITM3 with antigen processing and presentation, and cytokine signalling pathways. Chapter 4 characterises SARS-CoV-2-specific T cell responses in 42 COVID-19 convalescent patients. We observed broad and strong memory T cell responses against SARS-CoV-2 and identified seven dominant CD8+ epitopes. Finally, I show work evaluating T cell responses to SARS-CoV-2 variants of concern (VoCs) in a small cohort of COVID-19 convalescent patients and uninfected donors vaccinated with ChAdOx1. We established two systems to evaluate T cell responses to naturally processed and presented SARS-CoV-2 spike antigens using recombinant vaccinia virus and live SARS-CoV-2 virus. We found that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations in VoCs.