Alternative splicing expands the antiviral IFITM repertoire in Chinese horseshoe bats

Abstract

The interferon response is shaped by the evolutionary arms race between hosts and the pathogens they carry. The human interferon-induced transmembrane protein (IFITM) family consists of three antiviral IFITM genes that arose by gene duplication, they restrict virus entry and are key players of the interferon response. Yet, little is known about IFITMs in other mammals. Here, we identified an IFITM gene in Chinese horseshoe bat, a natural host of SARS-coronaviruses, that is alternatively spliced to produce two IFITM isoforms. These bat IFITMs have conserved structures in vitro and differential antiviral activities against influenza A virus and coronaviruses including SARS- and MERS-coronavirus. In parallel with human IFITM1-3, the bat IFITM isoforms localize to distinct cellular compartments. Further analysis of IFITM repertoires in 205 mammals reveals that alternative splicing is a ubiquitous strategy for IFITM diversification, albeit less widely adopted than gene duplication. These findings showcase an example of convergent evolution where species-specific selection pressures led to expansion of the IFITM family through multiple means, underscoring the importance of IFITM diversity as a component of innate immunity.