Evidence for a sex-dependent effect modification in the association between IFN-λ DNA polymorphisms and expression of IFN-λ and interferon-stimulated genes in human PBMCs.

Human interferon (IFN) lambda (IFNL, IFN-L or IFN-λ) locus has several functional genetic variants but their role in regulating in vivo gene expression, and whether they associate with antiviral states in healthy individuals, is not clear. In this study, we recruited ∼550 healthy individuals belonging to both sexes, genotyped them for several IFNL genetic variants and measured, by qPCR, the expression of IFNL2/3, IFNL4 and four IFN-stimulated genes (ISGs) (MX1, OAS1, ISG15 and RSAD2) from their peripheral blood mononuclear cells (PBMC) both before and after stimulation with a viral mimic, poly I: C. We also measured secreted levels of several cytokines including IFN-λ1 and IFN-λ3 in poly I:C stimulated PBMCs.

IFN-λ3 is induced by and can inhibit parasite growth in cell line models but not in the mouse model, while it shows a significant association with leishmaniasis in humans.

The intracellular protozoan parasite causes debilitating human diseases that involve visceral and dermal manifestations. Type 3 interferons (IFNs), also referred to as lambda IFNs (IFNL, IFN-L, or IFN-λ), are known to play protective roles against intracellular pathogens at the epithelial surfaces. Herein, we show that induces IFN-λ3 in human as well as mouse cell line-derived macrophages.

Gender-dependent multiple cross-phenotype association of interferon lambda genetic variants with peripheral blood profiles in healthy individuals.

Background: Type III interferons (IFN), also called as lambda IFNs (IFN-λs), are antiviral and immunomodulatory cytokines that are evolutionarily important in humans. Given their central roles in innate immunity, they could be influencing other aspects of human biology. This study aimed to examine the association of genetic variants that control the expression and/or activity of IFN-λ3 and IFN-λ4 with multiple phenotypes in blood profiles of healthy individuals.

A Novel Inactive Isoform with a Restored Reading Frame Is Expressed from the Human Interferon Lambda 4 TT Allele at rs368234815.

The TT allele of the dinucleotide variant rs368234815 (TT/ΔG) abolishes the open reading frame (ORF) created by the ancestral ΔG allele of the human interferon lambda 4 () gene, thus preventing the expression of a functional IFN-λ4 protein. While probing the expression of IFN-λ4 in human peripheral blood mononuclear cells (PBMCs), using a monoclonal antibody that binds to the C-terminus of IFN-λ4, surprisingly, we observed that PBMCs obtained from TT/TT genotype individuals could also express proteins that reacted with the IFN-λ4-specific antibody. We confirmed that these products did not emanate from the paralog, IF1IC2 gene.

Distinct molecular phenotypes involving several human diseases are induced by IFN-λ3 and IFN-λ4 in monocyte-derived macrophages.

Human Interferon (IFN) lambda 3 (IFN-λ3) and IFN-λ4 are closely linked at the IFNL locus and show association with several diseases in genetic studies. Since they are only ~30% identical to each other, to better understand their roles in disease phenotypes, comparative studies are needed. Monocytes are precursors to macrophages (monocyte-derived macrophages; MDMs) that get differentiated under the influence of various immune factors, including IFNs.

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India.

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.

Functional genetic variants of the IFN-λ3 (IL28B) gene and transcription factor interactions on its promoter.

Interferon lambda 3 (IFN-λ3 or IFNL3, formerly IL28B), a type III interferon, modulates immune responses during infection/inflammation. Several human studies have reported an association of single nucleotide polymorphisms (SNP) in the IFNL3 locus with expression level of IFNL3. Previous genetic studies, in the context of hepatitis C virus infections, had predicted three regulatory SNPs: rs4803219, rs28416813 and rs4803217 that could have functional/causal roles.

Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes.

Human IFN-λ4 is expressed by only a subset of individuals who possess the ΔG variant allele at the dinucleotide polymorphism rs368234815. Recent genetic studies have shown an association between rs368234815 and different infectious and inflammatory disorders. It is not known if IFN-λ4 has immunomodulatory activity.

SARS-CoV-2 infection in India bucks the trend: Trained innate immunity?

SARS-CoV-2, the causative agent of COVID-19 pandemic caught the world unawares by its sudden onset in early 2020. Memories of the 1918 Spanish Flu were rekindled raising extreme fear for the virus, but in essence, it was the host and not the virus, which was deciding the outcome of the infection. Age, gender, and preexisting conditions played critical roles in shaping COVID-19 outcome.

Mutations in SARS-CoV-2 viral RNA identified in Eastern India: Possible implications for the ongoing outbreak in India and impact on viral structure and host susceptibility.

Direct massively parallel sequencing of SARS-CoV-2 genome was undertaken from nasopharyngeal and oropharyngeal swab samples of infected individuals in Eastern India. Seven of the isolates belonged to the A2a clade, while one belonged to the B4 clade. Specific mutations, characteristic of the A2a clade, were also detected, which included the P323L in RNA-dependent RNA polymerase and D614G in the Spike glycoprotein.

The Genetic Association of IFN-λs with Human Inflammatory Disorders Remains a Conundrum.

Type III Interferons (IFNs) or lambda IFNs (IFN-λs or IFNLs) although are primarily antiviral cytokines, may have roles to play in shaping immune responses, including those during inflammation. Genetic variants within the locus have been shown to be associated with various inflammatory conditions in humans ranging from metabolic to autoimmune and allergic diseases. The mechanism behind these genetic associations is not clear.

Identifying causal variants at the interferon lambda locus in case-control studies: Utilizing non-synonymous variant rs117648444 to probe the role of IFN-λ4.

Genetic variants at the interferon lambda (IFNL) locus have been associated with several human phenotypes in both disease and health. In chronic hepatitis C virus (HCV) infections, where the IFNL variants were first identified to be associated with response to interferon-α-ribavirin therapy, the available data clearly suggests that the causal variant could be the dinucleotide polymorphism rs368234815 that causes an open reading frame-shift in the IFNL4 gene resulting in expression of a functional IFN-λ4, a new type III IFN. In other human diseases/phenotypes where IFNL variants have been recently associated with, the causal mechanism remains unclear.

A functional IFN-λ4-generating DNA polymorphism could protect older asthmatic women from aeroallergen sensitization and associate with clinical features of asthma.

Lambda interferons (IFNLs) have immunomodulatory functions at epithelial barrier surfaces. IFN-λ4, a recent member of this family is expressed only in a subset of the population due to a frameshift-causing DNA polymorphism rs368234815. We examined the association of this polymorphism with atopy (aeroallergen sensitization) and asthma in a Polish hospital-based case-control cohort comprising of well-characterized adult asthmatics (n = 326) and healthy controls (n = 111).

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.

Roles for Transcription Factors Sp1, NF-κB, IRF3, and IRF7 in Expression of the Human IFNL4 Gene.

The expression of a biologically active human IFNλ4 depends on the presence of a frameshift deletion polymorphism within the first exon of the interferon lambda 4 (IFNL4) gene. In this report, we use the lung carcinoma-derived cell line, A549, which is genetically viable to express a functional IFNλ4, to address transcriptional requirements of the IFNL4 gene. We show that the GC-rich DNA-binding transcription factor (TF) specificity protein 1 (Sp1) is recruited to the IFNL4 promoter and has a role in induction of gene expression upon stimulation with viral RNA mimic poly(I:C).

Association of IL28B single nucleotide polymorphism rs8099917 with response to treatment in genotype 3 HCV-infected patients from India.

Background And Aim: IL28B gene polymorphisms have been associated with treatment-response (sustained virological response, SVR) in genotype 1 hepatitis C virus (HCV)-infected patients, but only with early phase of viral decline (rapid virological response, RVR) with genotype 3 HCV-infected patients. Association between IL28B variants and SVR in genotype 3 HCV- infected patients is unclear. Our study aimed to replicate the association of IL28Bsingle nucleotide polymorphism (SNP) rs8099917 with SVR and to validate its association with RVR in genotype 3 HCV-infected patients.

Genetic variants at the IFNL3 locus and their association with hepatitis C virus infections reveal novel insights into host-virus interactions.

Human genetic variation plays a critical role in both spontaneous clearance of and response to interferon (IFN)-based therapies against hepatitis C virus (HCV) as shown by the success of recent genome-wide association studies (GWAS). Several GWAS and later validation studies have shown that single nucleotide polymorphisms (SNPs) at the IFNL3 (formerly IL28B) locus on chromosome 19 are involved in eliminating HCV in human patients. No doubt that this information is helping clinicians worldwide in making better clinical decisions in anti-HCV therapy, but the biological mechanisms involving the SNPs leading to differential responses to therapy and spontaneous clearance of HCV remain elusive.

A single nucleotide polymorphism associated with hepatitis C virus infections located in the distal region of the IL28B promoter influences NF-κB-mediated gene transcription.

Persistence of hepatitis C virus (HCV) infection is observed only in a subset of infected individuals and among them only some respond to treatment. Genome-wide association studies (GWAS) carried out around the world identified single nucleotide polymorphisms (SNPs) in the IL28B locus that are strongly associated with both HCV clearance and treatment response. The functional significance of these associations however, is not clear.

Mutations in the hepatitis C virus polymerase that increase RNA binding can confer resistance to cyclosporine A.

Unlabelled: Hepatitis C virus (HCV) infection leads to acute and chronic liver diseases, and new classes of anti-HCV therapeutics are needed. Cyclosporine A (CsA) inhibits HCV replication and CsA derivatives that lack the immunosuppressive function are currently in clinical trials as candidate anti-HCV drugs. Here we characterize several independently derived HCV replicons with varying levels of CsA resistance due to mutations in nonstructural protein 5B (NS5B), the HCV-encoded polymerase.

Impaired replication of hepatitis C virus containing mutations in a conserved NS5B retinoblastoma protein-binding motif.

Hepatitis C virus (HCV) downregulates the retinoblastoma tumor suppressor protein (Rb), a central cell cycle regulator which is also targeted by oncoproteins expressed by DNA tumor viruses. HCV genome replication is also enhanced in proliferating cells. Thus, it is possible that HCV interactions with host cell cycle regulators, such as Rb, have evolved to modify the intracellular environment to promote viral replication.

A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase.

Mutational analysis of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) template channel identified two residues, Trp(397) and His(428), which are required for de novo initiation but not for extension from a primer. These two residues interact with the Delta1 loop on the surface of the RdRp. A deletion within the Delta1 loop also resulted in comparable activities.