Rotavirus infections are associated with outbreaks of acute gastroenteritis. Non-dividing highly differentiated enterocytes, located at the tips of small intestinal villi, are the primary targets of rotavirus infection. Infants or young children infected with Rotavirus may develop severe diarrhea, become dehydrated and require hospitalization. Despite the broad uses of rotavirus vaccines, rotavirus infections are still one of the leading causes of death among infants and young children nowadays. Host initiates its innate immune responses through pattern recognition receptors (PPRs) after detects rotavirus invasion. Interferons (IFNs) are considered to be one of the most essential mediators, and serve as the first frontline defense against viral infections. Our lab activated the innate immunity through a bacterial-derived activator, flagellin, and in turn, the immediate immune responses were able to prevent and eliminate rotavirus infection. Interesting, flagellinmediated antiviral protection was neither dependent on interferon signaling nor adaptive immunity but rather elicited by secretion of interleukin (IL)-22 and IL-18, through activation of Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4) signaling, respectively. IL-22 promoted overall turnover (proliferation, migration and extrusion) rate of the intestinal epithelial cells (IEC), therefore, the extrusion process expelled the highly differentiated IEC that would preferentially succumb to rotavirus invasion. Meanwhile, IL-18 induced the programmed cell death among cells were infected by rotavirus, thus directly ceased the RV replication cycle. Understanding this novel antiviral mechanism will be essential for the exploration of prophylactic and therapeutic immunomodulatory strategy to substantiate existing medical intervention towards the treatment of viral infectious disease.