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Interferon-? 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 although the cytokines interferon-? (IFN-?) and IFN-? prevented the systemic spread of murine norovirus (MNoV), only IFN-? controlled persistent enteric infection. Infection-dependent induction of IFN-? was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFN-? cured mice in a manner requiring nonhematopoietic cell expression of the IFN-? receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFN-? for curing virus infections in the gastrointestinal tract.

SUBMITTER: Nice TJ

PROVIDER: S-EPMC4398891 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Nice Timothy J TJ Baldridge Megan T MT McCune Broc T BT Norman Jason M JM Lazear Helen M HM Artyomov Maxim M Diamond Michael S MS Virgin Herbert W HW

Science (New York, N.Y.) 20141127 6219

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 although 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 corre ...[more]

PMID: 25431489

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Project description:Background: Norovirus, also known as the winter vomiting bug, is the predominant cause of non-bacterial gastroenteritis worldwide. Disease control is predicated on a robust innate immune response during the early stages of infection. Double-stranded RNA intermediates generated during viral genome replication are recognised by host innate immune sensors in the cytoplasm, activating the strongly antiviral interferon gene programme. Ifit proteins (interferon induced proteins with tetratricopeptide repeats), which are highly expressed during the interferon response, have been shown to directly inhibit viral protein synthesis as well as regulate innate immune signalling pathways. Ifit1 is well-characterised to inhibit viral translation by sequestration of eukaryotic initiation factors or by directly binding to the 5' terminus of foreign RNA, particularly those with non-self cap structures. However, noroviruses have a viral protein, VPg, covalently linked to the 5' end of the genomic RNA, which acts as a cap substitute to recruit the translation initiation machinery. Methods: Ifit1 knockout RAW264.7 murine macrophage-like cells were generated using CRISPR-Cas9 gene editing. These cells were analysed for their ability to support murine norovirus infection, determined by virus yield, and respond to different immune stimuli, assayed by quantitative PCR. The effect of Ifit proteins on norovirus translation was also tested in vitro. Results: Here, we show that VPg-dependent translation is completely refractory to Ifit1-mediated translation inhibition in vitro and Ifit1 cannot bind the 5' end of VPg-linked RNA. Nevertheless, knockout of Ifit1 promoted viral replication in murine norovirus infected cells. We then demonstrate that Ifit1 promoted interferon-beta expression following transfection of synthetic double-stranded RNA but had little effect on toll-like receptor 3 and 4 signalling. Conclusions: Ifit1 is an antiviral factor during norovirus infection but cannot directly inhibit viral translation. Instead, Ifit1 stimulates the antiviral state following cytoplasmic RNA sensing, contributing to restriction of norovirus replication.

Dataset Information

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

Publications

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

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