TGF-β and Iron Differently Alter HBV Replication in Human Hepatocytes through TGF-β/BMP Signaling and Cellular MicroRNA Expression

The nature of host-virus interactions in hepatitis B virus infection is incompletely understood. Since soluble factors, e.g., cytokines and metals, may exacerbate liver injury in chronic hepatitis, we considered that defining the effects of receptor-mediated signaling upon viral replication will be significant. Consequently, we studied effects of iron or TGF-β-induced TGF-β/BMP signaling in the HepG2 2.2.15 cell model of hepatitis B virus replication. We found iron and TGF-β increased hepcidin mRNA expression or TGF-β receptor kinase activity, respectively, which indicated that 2.2.15 cells responded appropriately to these substances. However, iron increased but TGF-β decreased hepatitis B virus mRNA and DNA expression. TGF-β induced expression at the mRNA level of multiple TGF-β/BMP pathway genes. This change was not observed in iron-treated cells. On the other hand, presence of SMAD proteins in iron or TGF-β-treated cells, including of SMAD4, did confirm convergence of TGF-β/BMP signaling pathways under these conditions. Since transcription factors in TGF-β/BMP signaling pathways could not have directly targeted hepatitis B virus itself, we studied whether iron or TGF-β exerted their effects through alternative mechanisms, such as by involvement of antiviral cellular microRNAs. We discovered cellular microRNA expression profiles were significantly different in iron or TGF-β-treated cells compared with untreated control cells. In many cases, exposure to iron or TGF-β changed microRNA expression in opposite directions. Introduction in cells of sequences representing such differentially expressed microRNAs, e.g., hsa-miR-125a-5p and -151-5p, even reproduced effects on virus replication of iron- or TGF-β. We surmised that TGF-β/BMP pathway members, i.e., SMADs, likely governed iron or TGF-β-induced microRNA expression. Iron may have mediated Drosha/DGCR8/heme-mediated processing of microRNAs. In turn, cellular microRNAs regulated replication of hepatitis B virus in iron or TGF-β-treated cells. This knowledge should advance studies of mechanisms in viral-host interactions, hepatic injury, and therapeutic developments for hepatitis B

Production of lipopolysaccharide-induced tumour necrosis factor during influenza virus infection in mice coincides with viral replication and respiratory oxidative burst

Increased morbidity and mortality occur regularly during influenza epidemics. The exact mechanisms involved are not well defined but bacterial superinfection of influenza virus infected patients is considered to play an important role. In the present study, the effect of influenza virus infection on in vivo production of turnout necrosis factor (TNF) in response to bacterial stimuli was investigated. Release of TNF in mice infected by an aerosol of influenza virus was significant after administration of bacterial lipopolysaccharide (LPS) at 72 h, whereas administration of homologous influenza virus produced only modest amounts of TNF at 96 h. Significant production of TNF was observed 48 h after intravenous administration of infectious influenza in response to LPS but not with the homologous virus. TNF induced after influenza virus infection could be blocked by a specific murine anti-TNF monoclonal antibody. Higher TNF production following aerosol influenza infection correlated with peak titres of influenza virus in the lungs of infected mice and with enhanced generation of luminoldependent chemiluminscence