Comparative study of antiviral IFITM proteins in reservoir bat species

Abstract

Species-specific innate immune responses are shaped by the virus-host arms race and contribute to the species barrier against zoonosis. Interferon-induced transmembrane proteins (IFITMs) are key players in the antiviral interferon response and act by inhibiting viral entry. The unique IFITM repertoires of different species may influence their resistance to viral infections. Bats are reservoir hosts for many zoonotic viruses and their enhanced antiviral immunity has been proposed to be important for this, but whether IFITMs play a role is unclear. In this thesis, the comparative analysis of mammalian IFITM families reveals frequent IFITM gene duplication events, highlighting the importance of IFITM diversity as a component of innate immunity. An important functional motif, the amphipathic helix, has reduced amphipathicity in bat IFITMs which is predicted to alter their antiviral activity. Characterisation of IFITMs in Chinese rufous horseshoe bat, a natural host of SARS-related coronaviruses, shows that alternatively spliced IFITM isoforms can exhibit distinct antiviral specificities against influenza A virus, Nipah virus and coronaviruses including MERS-CoV, SARS-CoV and SARS-CoV-2. Besides their antiviral function, IFITMs can modulate interferon production, suggesting that they have effects beyond restricting viral entry that may also influence viral immunopathogenesis. Further bioinformatic analysis in 206 mammals reveals that IFITM alternative splicing is an underappreciated evolutionary strategy to generate diversity and is more prevalent in bats relative to other mammals. Increased frequency of alternative splicing is also evident in immune-related genes in humans which is consistent with the selection pressures imposed by the virus-host arms race. These findings identify alternative splicing as a key source of functional innovation in immunity and a strategy that may be used by reservoir bat species to fine-tune their antiviral immune response by regulating the expression of functionally distinct IFITM isoforms. My comparative analysis showcases the power of this approach to uncover novel features of gene functions. Similar studies to understand the unique antiviral immune responses in bats can guide the development of therapeutic strategies to treat viral infections and immunopathologies.