IFN-λ Research Articles

The impact of genetic variation in IL28B, IFNL4 and HLA genes on treatment responses against chronic hepatitis C virus infection

Single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B), interferon lambda 4 (IFNL4) and the human leukocyte antigen (HLA) gene are associated with treatment responses in patients with chronic hepatitis C (CHC) virus infection treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). We compared the role of IL28B SNPs (rs12979860, rs12980275, and rs8099917), IFNL4 ss469415590 and HLA rs4273729 with treatment outcomes in patients with CHC virus. A total of 520 Iranian patients with CHC infection were enrolled. SNPs in IL28B, IFNL4 ss469415590 and HLA rs4273729 were genotyped by PCR-restriction fragment length polymorphism, TaqMan® Real-Time PCR and direct sequence. Out of 520 CHC treatment-naive patients, 42.9% were infected with HCV-1a, 15.4% with HCV-1b, 9.8% with HCV-2, and 31.9% with HCV-3a. Rapid virologic response (RVR), complete early virologic response (cEVR), and sustained virologic response (SVR) were 53.3%, 73.8%, and 66.7%, respectively. Multivariate logistic regression analysis showed that IL28B rs12980275 and IFNL4 ss469415590 in all HCV genotypes were associated with RVR. In addition, IL28B rs12979860 and RVR in all HCV genotypes and IL28B rs12980275, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a correlated with cEVR. In patient's achieving-SVR, IL28B rs12980275, and RVR in all HCV genotypes and IL28B rs12979860, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a were the powerful predictor factors. As the first report of its kind published in Iran, we indicated that beside IL28B SNPs and HLA rs4273729, IFNL4 ss469415590 was a powerful predictor factor for RVR, cEVR and SVR. Genotyping these SNPs may be a helpful priority in the treatment of patients with HCV infection, especially in countries where access to triple or double therapy with a viral protease inhibitor is limited.

Confounding by Single Nucleotide Polymorphism rs117648444 (P70S) Affects the Association of Interferon Lambda Locus Variants with Response to Interferon-α-Ribavirin Therapy in Patients with Chronic Genotype 3 Hepatitis C Virus Infection

Genome-wide association studies discovered interferon lambda (IFNL or IFN-λ) locus on chromosome 19 to be involved in clearance of chronic hepatitis C virus (HCV) infection in patients following interferon-α-ribavirin (IFN-RBV) therapy. Subsequent studies established a dinucleotide polymorphism rs368234815, as the prime causal variant behind this association. The ΔG allele of this variant gives rise to a new IFNL gene, IFNL4, coding for IFN-λ4 whose activity paradoxically associates with lesser viral clearance rates. A low-frequency, nonsynonymous single nucleotide polymorphism (SNP) rs117648444 within the 2nd exon of IFNL4 changes the 70th amino acid from proline to serine resulting in lower activity of the functional IFN-λ4 protein, thereby increasing HCV clearance rates. In the present study, we used a cohort of genotype 3 HCV-infected patients, drawn from different geographical regions of India who underwent IFN-RBV therapy, to examine the association of several important IFNL locus SNPs/variants with sustained virological response (SVR). Intriguingly, the causal variant rs368234815 did not show the best strength and significance of association with SVR, while further analysis revealed that a negative confounding effect of rs117648444 was responsible for this phenomenon. Our results indicate that IFNL locus SNPs are subject to either a positive or a negative confounding effect by rs117648444; the nature of confounding depends on the linkage of the IFNL SNPs with the low-activity IFN-λ4-generating minor allele of rs117648444. Thus, our work demonstrates that the linkage disequilibrium structure of the IFNL region may confound the results of association studies. These results have implications for the design and understanding of future case-control studies involving IFNL locus SNPs/variants.

EGFR rs11506105 and IFNL3 SNPs but not rs8099917 are strongly associated with treatment responses in Iranian patients with chronic hepatitis C

Interferon lambda 3 (IFNL3) and epidermal growth factor receptor (EGFR) single nucleotide polymorphisms (SNPs) may play a key role in the spontaneous clearance of hepatitis C virus (HCV) and treatment responses. The aim of this study was to evaluate the effect of IFNL3 SNPs and EGFR rs11506105 on treatment outcomes in patients with chronic HCV (CHC). IFNL3 SNPs and EGFR rs11506105 were genotyped by PCR-restriction fragment length polymorphism and PCR-sequencing, respectively, in 235 naïve patients with CHC infection. The frequency of rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) were 52.3%, 76.2% and 64.7% respectively. The results of this study showed that RVR was associated with ALT (P=0.015), AST (P=0.020), IFNL3 rs12979860 (CC) (P=0.043), rs12980275 (AA) (P=1 × 10-4), and EGFR rs11506105 (AA) (P=0.010), and IFNL3 rs12979860 (CC) (P=0.048), rs12980275 (AA) (P=0.022), and EGFR rs11506105 (AA) (P=0.006) were correlated with cEVR. HCV genotype (P=0.007), IFNL3 rs12979860 (CC) (P=0.023), IFNL3 rs12980275 (AA) (P=1 × 10-4), EGFR rs11506105 (AA) (P=0.005), RVR (P=1 × 10-4), and cEVR (P=0.003) were significant predictors for SVR. These results, for the first time, revealed that beside IFNL3 SNPs, EGFR rs11506105 is strongly associated with RVR, cEVR and SVR. EGFR rs11506105 besides IFNL3 SNPs could predict treatment responses in CHC patients.

Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

IntroductionChronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.MethodsNIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0–2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.ResultsSeven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).ConclusionThe identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

The Central Conserved Region (CCR) of Respiratory Syncytial Virus (RSV) G Protein Modulates Host miRNA Expression and Alters the Cellular Response to Infection.

Respiratory Syncytial Virus (RSV) infects respiratory epithelial cells and deregulates host gene expression by many mechanisms including expression of RSV G protein (RSV G). RSV G protein encodes a central conserved region (CCR) containing a CX3C motif that functions as a fractalkine mimic. Disruption of the CX3C motif (a.a. 182–186) located in the CCR of the G protein has been shown to affect G protein function in vitro and the severity of RSV disease pathogenesis in vivo. We show that infection of polarized Calu3 respiratory cells with recombinant RSV having point mutations in Cys173 and 176 (C173/176S) (rA2-GC12), or Cys186 (C186S) (rA2-GC4) is associated with a decline in the integrity of polarized Calu-3 cultures and decreased virus production. This is accompanied with downregulation of miRNAs let-7f and miR-24 and upregulation of interferon lambda (IFNλ), a primary antiviral cytokine for RSV in rA2-GC12/rA2-GC4 infected cells. These results suggest that residues in the cysteine noose region of RSV G protein can modulate IFN λ expression accompanied by downregulation of miRNAs, and are important for RSV G protein function and targeting.

Vitamin D receptor polymorphisms as predictors of response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C infection

Objective The aim of the present study was to assess the influence of polymorphisms in vitamin D receptors (VDRs) Fok1 and Apa1 and interleukin 28B rs12979860 C/T on the response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C. Background Vitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus. Genetic polymorphisms affecting the VDR gene have been implicated in several immune disorders. Patients and methods This retrospective study was conducted on 80 patients who were divided into two groups: group I – the nonresponders group – comprised 40 patients and group II – the sustained virological response (SVR) group – also comprised 40 patients. The present study also included 20 healthy volunteers as controls. Two single nucleotide polymorphisms in VDRs Fok1 and Apa1 and in IL28B rs12979860 C/T) were determined by real-time PCR and restriction fragment length polymorphisms. Results Genotypes of IL28B rs12979860 (CC/CT/TT) were found in 23 (57.5%), 15 (37.5%), and two (5%) patients and of Apa1 (CA/AA/CC) in 24 (60%), 14 (35%), and two (5%) patients. Genotypes of Fok1 (TT/CC/TC) were found in 23 (57.5%), nine (22.5%), and eight (20%) patients, respectively, in the SVR group. Regarding IL28B rs12979860 polymorphisms, patients with a T-allele carrier had higher frequency among nonresponders (87.5%) in comparison with SVR (42.5%). Regarding VDR (Fok1) polymorphisms, patients with a C-allele carrier had higher frequency among nonresponders (92.5%) in comparison with SVR (42.5%). Regarding VDR Apa1 polymorphisms, patients with a C-allele carrier had higher frequency among nonresponders (92.5%) in comparison with SVR (65%). Conclusion Pretreatment vitamin D level was significantly higher in responders, and this can be used as a predictor of response to combination therapy for hepatitis C virus. VDR gene polymorphisms (Fok1 and Apa1) and IL28B rs12979860 polymorphism are independently related to response to interferon/ribavirin-based therapy in chronic hepatitis C.

Antiviral immunity: IFNλ offers frontline protection.

Lambda interferons have a non-redundant role in protecting airway epithelial cells from influenza A virus infection without inducing immunopathology.

IFN-\u03bb4 potently blocks IFN-\u03b1 signalling by ISG15 and USP18 in hepatitis C virus infection

Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-α-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-ΔG genotype, which encodes functional IFN-λ4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-λ4 in HCV-infected hepatocytes and their association with responsiveness to IFN-α. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-λ4 expression and IFN-α responsiveness. HCV infection induced IFN-λ4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-λ4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-α signalling. The ISG15/USP18-mediated IFN-α unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-λ4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-λs, including IFN-λ4, and restored IFN-α responsiveness. These results demonstrate that virus-induced IFN-λ4 potently blocks IFN-α signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-α responsiveness in HCV-infected cells.

The dynamic changes of interferon lambdas related genes and proteins in JAK/STAT pathway in both acute and chronic HIV-1 infected patients

BackgroundHost immune responses during acute HIV-1 infection can influence the viral setpoint, which is a predictor of disease progression. Interferon (IFN)-lambdas are newly classified type III interferons, which use JAK-STAT pathway. Currently, the dynamics of IFN-lambdas related genes and proteins expression in the signaling pathway have not been well elaborated, especially in acute HIV-1-infected patients.ObjectivesTo evaluate the dynamic changes of IFN-lambdas related genes and proteins in JAK/STAT pathway in acute HIV-1-infected patients, and analyze their correlation with CD4 T cell counts and HIV-1 viral loads.Study designReal-time PCR and flow cytometry methods were used to evaluate the dynamic changes of IFN-lambdas related genes and proteins in JAK/STAT pathway in both acute and chronic HIV-1-infected patients.ResultsThe IFN-alpha receptors (R), IFN-gamma R, IFN-lambdas R and STAT1 mRNA and protein levels increased in acute HIV-1-infected patients (p < 0.01), in addition, Mx1 mRNA levels in acute HIV-1-infected patients are higher than those in HIV-negative subjects. IFN-lambdas R and IFN-alpha R mRNA levels are inversely correlated with CD4+ T-cell counts, but are positively correlated with viral loads.ConclusionsThe dynamic changes of IFNs related genes in JAK-STAT pathway in acute HIV-1 infection will deepen our understanding of the roles of IFN-lambdas in HIV pathogenesis.

Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice

Co-infection with hepatitis B (HBV) and D virus (HDV) is associated with the most severe course of liver disease. Interferon represents the only treatment currently approved. However, knowledge about the impact of interferons on HDV in human hepatocytes is scant. Aim was to assess the effect of pegylated interferon alpha (peg-IFNα) and lambda (peg-IFNλ), compared to the HBV-polymerase inhibitor entecavir (ETV) on all HDV infection markers using human liver chimeric mice and novel HDV strand-specific qRT-PCR and RNA in situ hybridization assays, which enable intrahepatic detection of HDV RNA species. Peg-IFNα and peg-IFNλ reduced HDV viremia (1.4 log and 1.2 log, respectively) and serum HBsAg levels (0.9-log and 0.4-log, respectively). Intrahepatic quantification of genomic and antigenomic HDV RNAs revealed a median ratio of 22:1 in untreated mice, resembling levels determined in HBV/HDV infected patients. Both IFNs greatly reduced intrahepatic levels of genomic and antigenomic HDV RNA, increasing the amounts of HDAg- and antigenomic RNA-negative hepatocytes. ETV-mediated suppression of HBV replication (2.1-log) did not significantly affect HBsAg levels, HDV productivity and/or release. In humanized mice lacking adaptive immunity, IFNs but not ETV suppressed HDV. Viremia decrease reflected the intrahepatic reduction of all HDV markers, including the antigenomic template, suggesting that intracellular HDV clearance is achievable.

Genetic variation in interleukin 28B rs8099917 and response to antiviral therapy in Moroccan patients with chronic hepatitis C

BackgroundSeveral studies have shown that the genetic host factors may affect the progression of hepatitis C (HCV) and has an effect on single nucleotide polymorphisms interleukin 28B (IL28B) gene in patients with based treatment of INF/RIB. ObjectivesThe aim of our study is to evaluate the rate of rs8099917 genotypes of IL28B and examine its impact on the responsive treatment among Moroccan patients with chronic Hepatitis C. Patients and methodsA total of 173 HCV-positive people who received PEG-IFN/RBV were recruited in this study in which IL28B polymorphisms were genotyped by sequencing. Resultsthe SVR rates of our study were 40% in patients with genotype 1 and 81% in those with genotype 2. The frequencies of the genotypes rs8099917 were 67.05% TT; 31.79% TG and 1.15% GG. ConclusionIn the patients with chronic HCV-genotype 1b and 2 infections, IL28B is significantly associated with the responsive treatment of PEG-interferon/ribavirin among Moroccan patients with chronic HCV infection.

Ebolavirus protein VP24 interferes with innate immune responses by inhibiting interferon-λ1 gene expression

Ebolaviruses (EBOV) cause severe disease with a recent outbreak in West Africa in 2014–2015 leading to more than 28 000 cases and 11 300 fatalities. This emphasizes the urgent need for better knowledge on these highly pathogenic RNA viruses. Host innate immune responses play a key role in restricting the spread of a viral disease. In this study we systematically analyzed the effects of cloned EBOV genes on the main host immune response to RNA viruses: the activation of RIG-I pathway and type I and III interferon (IFN) gene expression. EBOV VP24, in addition of inhibiting IFN-induced antiviral responses, was found to efficiently inhibit type III IFN-λ1 gene expression. This inhibition was found to occur downstream of IRF3 activation and to be dependent on VP24 importin binding residues. These results emphasize the importance of VP24 in EBOV infection cycle, making VP24 as an excellent target for drug development.

Role of IL28B genotype in the liver stiffness increase in untreated patients with chronic hepatitis C

The role of interleukin (IL)28B has been deepened in the treatment response to pegylated-interferon in patients affected by chronic hepatitis C (CHC). However, recently the IL28B genotypes were also related to hepatic fibrosis progression in untreated patients, using the liver biopsy. The aim of this prospective and longitudinal study was to assess the role of different IL28B genotypes in the liver stiffness progression in a cohort of untreated subjects affected by CHC.We included in this analysis all untreated patients affected by CHC and followed for at least 5years with the annual evaluation of liver stiffness using Fibroscan®. All enrolled subjects were genotyped for rs8099917 and rs12979860 IL28B polymorphisms.In the study period, 266 patients were considered. After 5years we observed the following median stiffness increases: 6.7kPa [5.1–7.8] in TT/CC, 4.9kPa [4.1–5.0] in TT/TC, 3.4kPa [3.2–3.8] in TG/TC and 1.7kPa [1.2–1.9] in GG/TT. These values were statistically significant in all groups (p<0.001). In the multivariate analysis resulted as predictive factors of liver stiffness progression the following: IL28B TT/CC genotype (OR=4.571; 95%IC=2.381–12.994; p<0.001) and IL28B GG/TT genotype (OR=0.510; 95%IC=0.289–0.712; p=0.007). In this study we evidenced that IL28B genotypes were associated with a different level of liver stiffness increase after 5years and could be used to select the patients who should be treated with priority.

Cross-species antiviral activity of goose interferon lambda against duck plague virus is related to its positive self-regulatory feedback loop.

Duck plague virus (DPV) is a virus of the Herpesviridae family that leads to acute disease with a high mortality rate in ducks. Control of the disease contributes to the development of poultry breeding. Type III IFN family (IFN-λs) is a novel member of the IFN family, and goose IFN-λ (goIFN-λ) is a newly identified gene whose antiviral function has only been investigated to a limited extent. Here, the cross-species antiviral activity of goIFN-λ against DPV in duck embryo fibroblasts (DEFs) was studied. We found that pre-treatment with goIFN-λ greatly increased the expression of IFN-λ in both heterologous DEFs and homologous goose embryo fibroblasts (GEFs), while differentially inducing IFNα- and IFN-stimulated genes. Additionally, a positive self-regulatory feedback loop of goIFN-λ was blocked by a mouse anti-goIFN-λ polyclonal antibody, which was confirmed in both homologous GEFs and goose peripheral blood mononuclear cells (PBMCs). The suppression of the BAC-DPV-EGFP by goIFN-λ in DEFs was confirmed by fluorescence microscopy, flow cytometry (FCM) analysis, viral copies and titre detection, which can be rescued by mouse anti-goIFN-λ polyclonal antibody incubation. Finally, reporter gene assays indicated that the cross-species antiviral activity of goIFN-λ against BAC-DPV-EGFP is related to its positive self-regulatory feedback loop and subsequent ISG induction. Our data shed light on the fundamental mechanisms of goIFN-λ antiviral function in vitro and extend the considerable range of therapeutic applications in multiple-poultry disease.

Zinc is a potent and specific inhibitor of IFN-\u03bb3 signalling

Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.

A prognostic model for development of significant liver fibrosis in HIV-hepatitis C co-infection.

BackgroundLiver fibrosis progresses rapidly in HIV-Hepatitis C virus (HCV) co-infected individuals partially due to heightened inflammation. Immune markers targeting stages of fibrogenesis could aid in prognosis of fibrosis.MethodsA case-cohort study was nested in the prospective Canadian Co-infection Cohort (n = 1119). HCV RNA positive individuals without fibrosis, end-stage liver disease or chronic Hepatitis B at baseline (n = 679) were eligible. A random subcohort (n = 236) was selected from those eligible. Pro-fibrogenic markers and Interferon Lambda (IFNL) rs8099917 genotype were measured from first available sample in all fibrosis cases (APRI ≥ 1.5 during follow-up) and the subcohort. We used Cox proportional hazards and compared Model 1 (selected clinical predictors only) to Model 2 (Model 1 plus selected markers) for predicting 3-year risk of liver fibrosis using weighted Harrell’s C and Net Reclassification Improvement indices.Results113 individuals developed significant liver fibrosis over 1300 person-years (8.63 per 100 person-years 95% CI: 7.08, 10.60). Model 1 (age, sex, current alcohol use, HIV RNA, baseline APRI, HCV genotype) was nested in model 2, which also included IFNL genotype and IL-8, sICAM-1, RANTES, hsCRP, and sCD14. The C indexes (95% CI) for model 1 vs. model 2 were 0.720 (0.649, 0.791) and 0.756 (0.688, 0.825), respectively. Model 2 classified risk more appropriately (overall net reclassification improvement, p<0.05).ConclusionsIncluding IFNL genotype and inflammatory markers IL-8, sICAM-1, RANTES, hs-CRP, and sCD14 enabled better prediction of the 3-year risk of significant liver fibrosis over clinical predictors alone. Whether this modest improvement in prediction justifies their additional cost requires further cost-benefit analyses.

IFN-λ4 induces a faster but more transient antiviral response compared to other type III interferons

Abstract IFN-λ4, a recently discovered type-III interferon (IFN), is genetically regulated, and has clinical significance because of its association with impaired clearance of hepatitis C virus (HCV) infection. Type-III IFNs play a critical role in the innate immune response to viral infections. Although IFN-λ4 induces a similar antiviral profile as other type-III IFNs, its specific contribution to the innate immune response is unclear. Delineating the functional properties of IFN-λ4 that distinguish it from other type-III IFNs may give insights into its unique role during HCV, and other infections. Here we compared antiviral responses induced by all four type-III IFNs in HepG2 cells. We show that IFN-λ4 attained 50% peak antiviral activity by 4 hours while other type-III IFNs were only at 20% of peak activity at this time. The rapid antiviral response induced by IFN-λ4 was followed by a sharp decline to less than 25% of peak activity within 24 hours, while activity of other type-III IFNs were still over 60% from peak. By comparing antiviral activity of IFN-λ4 and IFN-λ3 against Sendai virus infection in primary human hepatocytes, we show that IFN-λ4 had stronger antiviral activity than IFN-λ3 early in the course of infection, but comparable activity at later time points. We also show that despite its poor secretion, IFN-λ4 was significantly more potent than IFN-λ3 in inducible cell lines engineered to express either protein. In summary, we show that IFN-λ4 is more active during the early stages of viral infection compared to other type-III IFNs, which maybe a clinically important window for restricting viral infection in the host, and affecting disease outcome.

Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness

Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1-/- mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.

The role of interferon lambda during influenza, Staphylococcus aureus super-infection.

Abstract While pandemic influenza A H1N1 infection causes significant morbidity and mortality on its own, it also renders an individual more susceptible to secondary infection with bacterial pathogens such as Staphylococcus aureus. We have previously shown that type I interferons produced by influenza impair bacterial defense six to seven days post-influenza infection. However, the role of the predominant type III interferons (interferon lambda/IFNL, IL-28A/B) in bacterial super-infection is less clear. Thus, we explored the role of IFNL in influenza, S. aureus super-infection. First, we examined the impact of attenuating IFNL signaling directly before bacterial challenge. We found that treatment with the IFNLR1 Fc protein significantly increased bacterial burden in the lung compared with controls. However, when we challenged mice with super-infection that have constitutively attenuated IFNL, we found reduced bacterial burden compared to controls, which was significantly correlated with the degree of IFNL expression. While cellular inflammation was not altered, preliminary results suggest that higher bacterial burden is significantly correlated with higher weight loss, suggesting that mice with constitutively attenuated IFNL are protected from both influenza infection and bacterial super-infection. It has been published that mice lacking IFNL receptor 1 have lower bacterial burden during super-infection, which is corroborated by data from our constitutively attenuated IFNL mice. However, attenuation of IFNL signaling directly prior to bacterial challenge increases bacterial burden, suggesting that the timing of IFNL production regulates susceptibility to secondary bacterial infection.

Role of Interferons in Chronic Hepatitis C Infection

It is known that the production of and/or response to interferon (IFN) are deregulated during chronic hepatitis C virus (HCV) infection. In particular, several studies have shown that patients with chronic HCV infection who have a high natural level of IFN-stimulated genes (ISGs) do not achieve viral clearance and have a poor response to treatment with pegylated IFNα and ribavirin. The viral and/or host factors that are responsible for the higher endogenous ISGs expression in some HCV infected patients compared to others remain to be determined. However, type III IFNs, and in particular the new discovered IFN lambda (L) 4 Gene, appear to play a dominant role in driving ISGs response and in contributing to the establishment of HCV persistence. This review focuses on recent studies on how the ISGs response and the IFNλ genetic factors (interleukin-28B and IFNL4) affect the clinical outcome of HCV infection highlighting their impact in the current antiviral therapies with direct acting antiviral agents.