Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections

Lee, Sanghyun; Baldridge, Megan T.

immunocompromised individuals (55), who can potentially seed future epidemics (56) . Until quite recently, human NoV has been impractical to culture in vitro (57, 58) and lacked a robust small animal model. Secondary to these challenges, the role of IFN-λ in control of human NoV in vivo is unknown. In vitro, human NoV RNA replication and virus production, after transfection of stool-isolated RNA into mammalian cells, is sensitive to treatment with type I and III IFNs (59) . However, in this system, NoV RNA replication does not induce IFNs or respond to neutralization of type I or III IFNs (59) . Whether this reflects the in vivo effects of NoV infection remains to be seen. The discovery of murine NoV (MNoV) (60) , which is readily culturable (61) and can be studied in vivo, facilitated exploration of the interactions between NoV and the host immune system (62) . IFNs have long been known to be important in MNoV regulation, as the virus was originally isolated from and causes severe disease and death in Stat1-deficient mice (60, 63) . Type I and II IFNs both control acute, systemically spreading strains of MNoV [recently reviewed in Ref. (62) ]. By contrast, type I and II IFNs are dispensable for intestinal regulation of persistent strains of MNoV (64) , which replicate robustly in the colon and are shed at high levels in the stool (65) . Instead, for persistent MNoV, IFN-λ plays a critical regulatory role. Endogenous IFN-λ controls intestinal viral replication and shedding, demonstrated by increased shedding in Ifnlr1-deficient mice. In addition, exogenous IFN-λ prevents and cures persistent MNoV infection in wild-type and Rag1-deficient mice (64) . Thus, IFN-λ represents an example of sterilizing innate immunity. Because myeloid and B cells, which support MNoV replication in vitro (57, 61) , and IECs, the target cells of IFN-λ for MNoV clearance (50) , are distinct, it remains to be determined whether in vivo IFN-λ stimulates an antiviral program in a cell-intrinsic fashion to clear infected IECs, or instead drives production of secondary factors to target infected myeloid or B cells.