Impact of alcohol on hepatitis C virus replication and interferon signaling

Hepatitis C virus (HCV) is one of the main etiological factors responsible for liver disease worldwide. It has been estimated that there are over 170 million people infected with HCV worldwide. Of these infected individuals, approximately 75% will go on to develop a life long necroinflammatory liver disease, which over decades, can result in serious complications, such as cirrhosis and hepatocellular carcinoma. Currently there is no effective vaccine and whilst antiviral therapies have been improved, they are still only effective in approximately 50% of individuals. HCV infection stands as a major cause of global morbidity and suffering, and places a signifi cant burden on health systems. The second highest cause of liver disease in the western world is alcoholic liver disease. Frequently, HCV infected individuals consume alcohol, and the combined effect of HCV and alcohol consumption is deleterious for both liver disease and response to treatment. This review discusses the impact of alcohol metabolism on HCV replication and the negative impact on interferon (IFN)-α treatment, with a particular focus on how alcohol and HCV act synergistically to increase oxidative stress, ultimately leading to exacerbated liver disease and a reduction in the effi cacy of IFN-α treatment. A better understanding of the complicated mechanisms at play in hepatocytes infected with HCV and metabo- lizing alcohol will hopefully provide better treatment options for chronic hepatitis C individuals that consume alcohol.

Expression level of interferon-stimulated genes PKR,OAS1,MX1,and ISG15 in peripheral blood mononuclear cells of COVID-19 patients:A retrospective study

Objective:To explore expression level of interferon-stimulated genes PKR,OAS1,MX1,and ISG15 in peripheral blood mononuclear cells of COVID-19 patients.Methods:In this study,changes in the expression of four interferon-stimulated genes(ISGs),including PKR,OAS1,MX1,and ISG15,in peripheral blood mononuclear cells of 45 COVID-19 patients with different severities were evaluated by real-time PCR method.Results:OAS1,MX1,PKR,and ISG15 were differently expressed in COVID-19 patients with different severity.The results showed that the expression of OAS1,MX1,PKR,and ISG15 genes was significantly(P=0.001)lower in severe patients.Conclusions:Weak and defective IFN response and subsequent disruption of ISGs may be associated with COVID-19 severity.

Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication

As one of the deadliest viruses,Ebola virus(EBOV)causes lethal hemorrhagic fevers in humans and nonhuman primates.The suppression of innate immunity leads to robust systemic virus replication of EBOV,leading to enhanced transmission.However,the mechanism of EBOV-host interaction is not fully understood.Here,we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis,which are highly clustered to Jak-STAT signaling.EBOV VP35 and VP30 were found to inhibit type I interferon(IFN)signaling.Moreover,exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1,and suppresses nuclear translocation of STAT1.Using serial truncated mutations of VP35,N-terminal 1–220amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling.Remarkably,VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus(BDBV)and Marburg virus(MARV),resulting in stable replication to facilitate the pathogenesis.Altogether,this study enriches understanding on EBOV evasion of innate immune response,and provides insights into the interplay between filoviruses and host.

SOCS3 acts as a potential negative regulator in the antiviral response of large yellow croaker(Larimichthys crocea)by interacting with STAT1

Suppressors of cytokine signaling(SOCS)proteins are important regulators of the Janus kinase-signal transducer and activator of transcription(JAK-STAT)pathway.Within the SOCS family,SOCS3 is one of the most potent inhibitors of cytokine signaling.However,there is limited knowledge regarding the function of SOCS3 on regulating type I interferon(IFN)signaling in fish.In this study,the complete open reading frame(ORF)of SOCS3 from the large yellow croaker(Larimichthys crocea,LcSOCS3)was cloned and characterized.The ORF of LcSOCS3 was 618 nucleotides in length and encoded a protein containing 205 amino acids.LcSOCS3 had the typical domain architecture of the SOCS family,including an SRC homology 2(SH2)domain,a SOCS box,an additional kinase inhibition region(KIR),and an extended SH2 subdomain(ESS).Phylogenetic analysis revealed that LcSOCS3 was clustered with other fish SOCS3s and most closely related to the SOCS3 of Collichthy lucidus.LcSOCS3 mRNA was detected in all organs or tissues examined,and its expression was significantly increased in both head kidney and spleen tissues,and primary head kidney leukocytes after poly(I:C)stimulation.Overexpression of LcSOCS3 significantly promoted Spring viremia of carp virus(SVCV)replication,resulting in a more severe cytopathic effect,increased viral titer,enhanced copy number of the SVCV-G gene,and decreased expression levels of IFN1,IRF7,ISG15,Viperin,PKR,and Mx in epithelioma papulosum cyprinid(EPC)cells.Silencing of LcSOCS3 correspondingly up-regulated the expression of IFNi,IFNh,PKR,Viperin,and Mx in large yellow croaker head kidney(LYCK)cells.Additionally,LcSOCS3 was shown to interact with Signal Transducer and Activator of Transcription 1(STAT1)which may inhibit STAT1 translocating into the nucleus.This speculation was supported by the increased phosphorylation level of STAT1 in head kidney leukocytes after LcSOCS3 silencing.These results indicated that LcSOCS3 functioned as a potential negative regulator of type I IFN signaling in large yellow croaker through its interaction with STAT1.

Long noncoding RNA 1392 regulates MDA5 by interaction with ELAVL1 to inhibit coxsackievirus B5 infection

Long noncoding RNAs(lncRNAs)modulate many aspects of biological and pathological processes.Recent studies have shown that host lncRNAs participate in the antiviral immune response,but functional lncRNAs in coxsackievirus B5(CVB5)infection remain unknown.Here,we identified a novel cytoplasmic lncRNA,LINC1392,which was highly inducible in CVB5 infected RD cells in a time-and dose-dependent manner,and also can be induced by the viral RNA and IFN-β.Further investigation showed that LINC1392 promoted several important interferon-stimulated genes(ISGs)expression,including IFIT1,IFIT2,and IFITM3 by activating MDA5,thereby inhibiting the replication of CVB5 in vitro.Mechanistically,LINC1392 bound to ELAV like RNA binding protein 1(ELAVL1)and blocked ELAVL1 interaction with MDA5.Functional study revealed that the 245–835 nt locus of LINC1392 exerted the antiviral effect and was also an important site for ELAVL1 binding.In mice,LINC1392 could inhibit CVB5 replication and alleviated the histopathological lesions of intestinal and brain tissues induced by viral infection.Our findings collectively reveal that the novel LINC1392 acts as a positive regulator in the IFN-I signaling pathway against CVB5 infection.Elucidating the underlying mechanisms on how lncRNA regulats the host innate immunity response towards CVB5 infection will lay the foundation for antiviral drug research.

MicroRNAs:Role in hepatitis C virus pathogenesis

Hepatitis C virus(HCV)is a global health burden with an estimated 170e200 million peoples chronically infected worldwide.HCV infection remains as an independent risk factor for chronic hepatitis,liver cirrhosis,hepatocellular carcinoma,and a major reason for liver transplantation.Discovery of direct acting antiviral(DAA)drugs have shown promising results with more than 90%success rate in clearing the HCV RNA in patients,although long-term consequences remain to be evaluated.microRNAs(miRNAs)are important players in establishment of HCV infection and target crucial host cellular factors needed for productive HCV replication and augmented cell growth.Altered expression of miRNAs is involved in the pathogenesis associated with HCV infection by controlling signaling pathways such as immune response,proliferation and apoptosis.miRNA is emerging as a means of communication between various cell types inside the liver.There is likely possibility of developing circulating miRNAs as biomarkers of disease progression and can also serve as diagnostic tool with potential of early therapeutic intervention in HCV associated end stage liver disease.This review focuses on recent studies highlighting the contribution of miRNAs in HCV life cycle and their coordinated regulation in HCV mediated liver disease progression.