IRF-1, RIG-I and MDA5 display potent antiviral activities against norovirus coordinately induced by different types of interferons

Abstract

Norovirus represents the main cause of acute nonbacterial gastroenteritis worldwide. In immunocompromised patients, it bears high risk of causing chronic infection with significant morbidity and mortality. The lack of specific treatment prompts the development of anti-norovirus agents. In this study, we have investigated the role of interferon (IFN) response and evaluated antiviral activities of different IFNs against human norovirus (HuNoV) replication using a HuNoV replicon model. We found that HuNoV RNA replication was sensitive to all types of IFNs, including IFNα (type I), IFNγ (type II), IFNλ1 and 3 (type III). IFNs canonically induce interferon-stimulated genes (ISGs) to exert their antiviral activities. By profiling a subset of important human ISGs using an overexpression approach, we have identified RTP4 and HPSE as moderate anti-norovirus ISGs, whereas IRF-1, RIG-I (also known as DDX58) and MDA5 (also known as IFIH1) were identified as potent anti-norovirus effectors. Interestingly, type I and III IFNs coordinately induced IRF-1, RIG-I and MDA5; whereas type II IFN predominantly induced IRF-1 to exhibit their anti-norovirus activities. Combination of different IFNs revealed that IFNγ worked cooperatively with type I or type III IFNs to induce ISGs and subsequently inhibit HuNoV replication. Of note, replication of HuNoV did not interfere with antiviral IFN response. In summary, we showed the potent anti-norovirus activities of different types of IFNs and identified the key anti-norovirus effectors. These findings are important for understanding norovirus-host interactions and developing antiviral therapies.

Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro

“…Similarly, down-regulation of ISRE-dependent genes in HGT-NV when compared to HGT-Cured cells, which have silenced the IFNLR1 gene to the same extent, put forward the idea that HuNoV replication induces IFN-dependent responses. In line with this, a recent study using the same replicon identified RIG-I and MDA5 proteins as potent negative regulator of HuNoV replication suggesting that viral RNA secondary structures can readily be detected during replication (Dang et al, 2018). These observations are however in striking contrast to the study of Qu and colleagues in which transfection of stool-derived HuNoV RNA readily replicated in 293T cells but failed to induce detectable interferon responses (Qu et al ., 2016).…”

“…Influence of lambda interferons on murine noroviruses has been highlighted in previous studies using different experimental setups (Baldridge et al ., 2015; Baldridge et al ., 2017; Rocha-Pereira et al ., 2018b). In the case of the human norovirus, recent work using the same replicon in Huh-7 human hepatoma cell line showed that all three types of IFN, when exogenously added, were able to inhibit HuNoV replication leading to virus clearance during long-term treatment (Dang et al ., 2018). However, it is not known whether physiological activation of the interferon pathways, particularly, the lambda IFN signalling pathway exerts an antiviral effect against human noroviruses.…”

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

“…RAD51AP1 facilitates homologous recombination of host DNA [107], while SEC61G functions in membrane protein translocation and incorporation into the endoplasmic reticulum [108]. The interactions between HuNoV and these genes are speculative; however IRF3 [109,110], IRF7 [110,111], MDA5 [112][113][114][115], RIG-I [35,111,113,114], TLR3 [112], and TLR7 [114,116,117] have been previously implicated in NoV responses. Of note, TLR2 enhances cytokine production upon the detection of rotavirus [118].…”

Plucked hair follicles from patients with chronic discoid lupus erythematosus show a disease-specific molecular signature

“…A molecular hallmark of lupus erythematosus lesions is the high expression of interferon (IFN)-stimulated genes (ISGs) 9 15 16. These include myxovirus protein A ( MxA ),17 IFN inducible protein 6 ( IFI6 ), CXCL9 , CXCL10 , 2,5-oligoadenylate synthase ( OAS ) including OAS2 and OASL , IFN-induced helicase C domain-containing protein 1 ( IFIH1/MDA5 ), bone marrow stromal antigen 2 ( BST2 ) and guanylate-binding protein 1 ( GBP1 ) in CLE lesions 8 18–21. It is well known that IFNs induce expression of major histocompatibility complex (MHC) class I and MHC class I-pathway related molecules (β2 microglobulin, β2M) and this has also been reported for organ-cultured human scalp skin 22–24.…”