Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections

Lee, Sanghyun; Baldridge, Megan T.

are required for type I IFN production by IECs during RV infection (42) ; induction pathways for IFN-λ have not been reported. IECs produce the majority of IFN-λ, consistent with the viral IEC tropism (16) . Pretreatment with exogenous IFN-λ effectively prevents EDIM-RV replication in the small intestine and colon (41) . However, a recent study demonstrated that a homologous murine strain of RV, EW-RV, is largely IFN-λ-insensitive, even though EW-RV is originally derived from EDIM-RV (24) . This study also showed that a heterologous rhesus strain of rotavirus (RRV) is, in contrast, highly sensitive to both IFN-α/β and IFN-λ, even though EW-RV and RRV infection both significantly induce IFN-α/β and IFN-λ production during infection (24) . The reason for this discrepancy between strains is still unclear, though recently, a human RV study using human intestinal enteroids provided some hints regarding the source of this strain complexity (43) . In this study, human RV infection in enteroids indeed induced IFN-λ and interferon-stimulated genes (ISGs). However, blocking IFN-λ signaling did not have any effect on viral growth. Since RV has multiple functional proteins for immune evasion (e.g., NSP1, NSP3, and VP3) (44) , the effect of IFN-λ may be limited by these viral genes, and EW-RV may utilize evasion strategies to overcome IFN responses. Thus, interactions between RV and IFN-λ in the intestine are influenced by multiple host and viral factors.