Human noroviruses are a major cause of acute gastroenteritis worldwide, but the 
lack of a robust cell culture system or small animal model have hampered a 
better understanding of innate immunity against these viruses. Tulane virus (TV) 
is the prototype virus of a tentative new genus, Recovirus, in the family 
Caliciviridae. Its epidemiology and biological properties most closely resemble 
human norovirus. The host innate immune response to RNA virus infection 
primarily involves pathogen-sensing toll-like receptors (TLRs) TLR3 and TLR7 and 
retinoic acid-inducible gene I-like receptor RIG-I and melanoma differentiation 
associated gene 5 (MDA5). In this study, by using siRNA knockdown, we report 
that TV infection in LLC-MK2 cells results in an early [3 h post infection (h 
p.i.), P<0.05] RIG-I-dependent and type I interferon-mediated antiviral 
response, whereas an MDA5-mediated antiviral effect was observed at later (12 h 
p.i.; P<0.05) stages of TV replication. Induction of RIG-I and MDA5 was critical 
for inhibition of TV replication. Furthermore, pre-activation of the RIG-I/MDA5 
pathway prevented TV replication (>900-fold decrease; P<0.05), suggesting that 
RIG-I and MDA5 ligands could be used to develop novel preventive and therapeutic 
measures against norovirus.