The single nucleotide polymorphism, rs1990760, in the cytosolic viral sensor, IFIH1, results in an amino-acid change (p.A946T) and is associated with multiple autoimmune diseases. The impact of this polymorphism on both viral-sensing and autoimmune pathogenesis remains poorly understood. Here, we find that human PBMCs and cell lines with the risk variant, IFIH1T946, exhibit heightened, basal and ligand-triggered type I interferon (IFN-I) production. Consistent with these findings, IFIH1T946 knock-in mice display enhanced basal IFN-I expression, survive a lethal viral challenge, and exhibit increased penetrance in autoimmune models including a combinatorial impact with other risk variants. Further, IFIH1T946 mice manifest an embryonic survival defect consistent with enhanced responsiveness to RNA self-ligands. Together, our data support a model wherein autoimmune risk variant-driven, ligand-triggered IFN-I production functions to protect against viral challenge, likely accounting for its selection within human populations, but provides this advantage at the cost of modestly promoting the risk for autoimmunity.
Background & Aims Liver sinusoidal endothelial cells (LSECs) make up a large proportion of the non-parenchymal cells in the liver. LSECs are involved in induction of immune tolerance, but little is known about their functions during hepatitis C virus (HCV) infection. Methods Primary human LSECs (HLSECs) and immortalized liver endothelial cells (TMNK-1) were exposed to various forms of HCV, including full-length transmitted/founder virus, sucrose-purified Japanese Fulminant Hepatitis-1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules. Cells were analyzed by confocal immunofluorescence, immunohistochemical, and PCR assays. Results HLSECs internalized HCV, independent of cell–cell contacts; HCV RNA was translated but not replicated. Through pattern recognition receptors (TLR7 and retinoic acid inducible gene 1), HCV RNA induced consistent and broad transcription of multiple interferons (IFNs); supernatants from primary HLSECs transfected with HCV-specific pathogen-associated molecular pattern molecules increased induction of IFNs and IFN-stimulated genes in HLSECs. Recombinant type I and type III IFNs strongly up-regulated HLSEC transcription of interferon λ 3 (IFNL3) and viperin (RSAD2), which inhibit replication of HCV. Compared to CD8+ T cells, HLSECs suppressed HCV replication within Huh7.5.1 cells, also inducing IFN-stimulated genes in co-culture. Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes. Exosomes, derived from HLSECs following stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner. Conclusions Cultured HLSECs produce factors that mediate immunity against HCV. HLSECs induce self-amplifying IFN-mediated responses and release of exosomes with antiviral activity.
Background Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection, however, potential mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in NK cell populations may explain altered natural history and treatment responses. Methods Our study cohort consisted of 29 African-American (AA, 55% male) and 29 Caucasian-American (CA, 48% male) normal uninfected control subjects. Multi-parameter flow-cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time RT-PCR after 6 hour in vitro stimulation with TLR ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 co-culture system. Results NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (p=0.0054). NKp46high NKs were more efficient at controlling HCV than their NKp46low counterparts (p<0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 co-culture (MOI 0.01) at an effector:target ratio of 5:1 (p<0.005). After TLR stimulation, genes involved in cytotoxicity but not cytokine genes were significantly upregulated in NKp46high NKs. Cytokine stimulation (IL-12 and IL-15) demonstrated that NKp46high NK cells have significantly higher IFN-γ production than NKp46low cells. TLR stimulation significantly induced degranulation as well as TRAIL, Fas and TNF-α protein expression in NKp46high NKs. NKp46 ligand was induced on HCV-infected hepatocytes . Conclusions NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target.
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