Fish TLR5 develops a taste for viral RNA.

These days not only humans but also freshwater fish battle with infections by RNA viruses (Zou & Nie, 2017). This observation prompted Liao et al to turn their attention to viral recognition in Grass carp (Ctenopharyngodon idella), the most important cultivated freshwater fish with 5.7 million tons and 13 billion USD in fishery exports per year (FAO, 2021). Grass carp and other freshwater fish, such as the model organism Danio rerio (zebrafish), have a sophisticated innate immune system that helps them to detect microbial and viral pathogens by employing a variety of pattern recognition receptors (PRRs; Zou & Nie, 2017). Toll-like receptors (TLRs) are one class of PRRs that detect microbe-associated molecular patterns (MAMPs), such as flagellin or viral double-stranded (ds)RNA. In mammals, TLR3 is specialized in sensing viral dsRNA (Liu et al, 2008), while TLR5 recognizes the MAMP flagellin (Yoon et al, 2012; Fig 1). The well-established notion of TLR5 as a purely "bacterial" flagellin TLR has now been challenged by Liao et al in this issue of EMBO Reports (Liao et al, 2022). The authors' intriguing and unexpected results indicate that fish TLR5 is involved in viral recognition, a function lost in mammals, and shed light on hitherto inexplicable links of mammalian TLR5 to antiviral immune signaling.