Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity

Abstract

Norovirus gastroenteritis is a major public health burden worldwide. Although fecal shedding is important for transmission of enteric viruses, little is known about the immune factors that restrict persistent enteric infection. We report here that while the cytokines interferon-α (IFN-α) and IFN-β prevented the systemic spread of murine norovirus (MNoV), only IFN-λ controlled persistent enteric infection. Infection-dependent induction of IFN-λ was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFN-λ cured mice in a manner requiring non-hematopoietic cell expression of the IFN-λ receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFN-λ for curing virus infections in the gastrointestinal tract.

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…Treatment with type I IFN-β was significantly more effective than type III IFN at restricting HRV replication. This differs from reports in mice, in which exogenous treatment with IFN-λ is more protective against enteric viral replication than type I IFN (55,56), and type I IFN is primarily considered to inhibit systemic spread of enteric viruses (17,56,75). This difference may be a result of the type I IFN subtype tested; previous studies in mice and HIEs used an IFN-α subtype rather than IFN-β for exogenous treatment (17,55,56,83); however, IFN-α2 was significantly weaker than IFN-β in restricting HRV growth in HIEs.…”

“…This result was unexpected because enteric viral replication (rotavirus, reovirus, murine norovirus) is enhanced in mice lacking the type III IFN receptor (54)(55)(56)75), even though it is notable that neutralization of the type III IFN response had a limited effect on reovirus replication (approximately twofold increase in viral transcripts) in a human colonic transformed cell line (70). The basis for the apparent discrepancy may be multifactorial and include differences in how the IFN system was blocked (neutralizing antibodies vs. receptor KOs), development of alternate compensatory pathways in IFN-KO mice, and/or differences in human and mouse type III IFN subtype expression (37,38).…”

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

“…Important areas of future research will be to determine whether the enterocytes transcytosing NoVs recognize pathogen-associated molecular patterns (PAMPs) and contribute to the antiviral immune response; and whether antiviral immune responses that prevent transcytosis are important in controlling NoV infection. Related to the latter idea, a recent report demonstrated that the type III interferon (IFN), or IFN-l, response is critical to control persistent enteric infection by MuNoVs in a manner requiring IFN-l receptor expression on nonhematopoietic cells 40 ; thus, one could speculate that IFN-l-mediated signaling suppresses transcytosis of NoVs and this prevents persistence establishment.…”

Treatment with a Nucleoside Polymerase Inhibitor Reduces Shedding of Murine Norovirus in Stool to Undetectable Levels without Emergence of Drug-Resistant Variants

“…The site of persistence is reported to be the intestine, where CR6 is present for many weeks after infection (20). It was recently shown that both wildtype and IFNAR Ϫ/Ϫ -positive mice were cured of an ongoing MNV.CR6 infection following treatment with gamma interferon (IFN-) (21).…”