Ubiquitination of pattern recognition receptors in plant innate immunity

Lacking an adaptive immune system, plants largely rely on plasma membrane‐resident pattern recognition receptors (PRRs) to sense pathogen invasion. The activation of PRRs leads to the profound immune responses that coordinately contribute to the restriction of pathogen multiplication. Protein post‐translational modifications dynamically shape the intensity and duration of the signalling pathways. In this review, we discuss the specific regulation of PRR activation and signalling by protein ubiquitination, endocytosis and degradation, with a particular focus on the bacterial flagellin receptor FLS2 (flagellin sensing 2) in Arabidopsis.     

Toll-like receptor signaling inhibits hepatitis B virus replication in vivo

Toll-like receptors (TLR) play a key role in innate immunity. To examine the ability of diverse TLRs to modulate hepatitis B virus (HBV) replication, HBV transgenic mice received a single intravenous injection of ligands specific for TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9. All of the ligands except for TLR2 inhibited HBV replication in the liver noncytopathically within 24 h in a alpha/beta interferon-dependent manner. The ability of these TLR ligands to induce antiviral cytokines at the site of HBV replication suggests that TLR activation could represent a powerful and novel therapeutic strategy for the treatment of chronic HBV infection.     

Lambda interferon inhibits hepatitis B and C virus replication

Lambda interferon (IFN-lambda) induces an intracellular IFN-alpha/beta-like antiviral response through a receptor complex distinct from the IFN-alpha/beta receptor. We therefore determined the ability of IFN-lambda to inhibit hepatitis B virus (HBV) and hepatitis C virus (HCV) replication. IFN-lambda inhibits HBV replication in a differentiated murine hepatocyte cell line with kinetics and efficiency similar to IFN-alpha/beta and does not require the expression of IFN-alpha/beta or IFN-gamma. Furthermore, IFN-lambda blocked the replication of a subgenomic and a full-length genomic HCV replicon in human hepatocyte Huh7 cells. These results suggest the possibility that IFN-lambda may be therapeutically useful in the treatment of chronic HBV or HCV infection.     

Inhibition of replication of human hepatitis B virus

Several nucleoside 5'-triphosphate analogs were investigated as inhibitors of human hepatitis B virus replication. Different analogs inhibited DNA synthesis differently, 3'-azido-2',3'-dideoxythymidine 5'triphosphate being the most active compound. This inhibitor blocked DNA synthesis by 50% at inhibitor: substrate molar ratio 1:8, and by 80% - at 1:1. The hypothesis is formulated that 3'-azido-2',3'-dideoxythymidine 5'-triphosphate inhibits RNA directed viral DNA replication due to incorporation of this compound into 3'-termini of newly synthesized DNA chains. The phenomenon observed opens new possibilities for chemotherapy of acute and chronic human hepatitis B.     

Core-APOBEC3C chimerical protein inhibits hepatitis B virus replication

We tested the capsid targeted viral inactivation method as an anti-HBV strategy. HepG2 cells were cotransfected with HBV expression plasmid and the plasmid encoding fusion protein of either Core-A3C or Core-humanized renilla GFP (hrGFP). Core-A3C had substantial effect on HBV DNA levels. In the HepG2 cells expressing Core-A3C, the number of G-to-A mutations increased dramatically, whereas other nucleotide substitutions were rare. In addition, Core-A3C substantially inhibited HBV production intracellularly and in culture supernatant. These results suggest that Core-A3C may be a candidate as a novel antiviral agent against human HBV infection.     

Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice

Interleukin-18 (IL-18) produced by activated antigen-presenting cells stimulates natural killer (NK) cells, natural killer T (NKT) cells, and T cells to secrete gamma interferon (IFN-gamma). In this study, injection of a single 10- micro g dose of recombinant murine IL-18 rapidly, reversibly, and noncytopathically inhibited hepatitis B virus (HBV) replication in the livers of HBV transgenic mice. Furthermore, HBV replication was inhibited by as little as 1 micro g of IL-18 injected repetitively, and also by a single 0.1- micro g dose of IL-18 injected together with 1 ng of IL-12, neither of which inhibited HBV replication individually, demonstrating synergy between these cytokines in this system. The antiviral effect of IL-18 was mediated by its ability to activate resident intrahepatic NK cells and NKT cells to produce IFN-gamma and by its ability to induce IFN-alpha/beta production in the liver. These results suggest that IL-18 has the potential to contribute to the control of HBV replication during self-limited infection and that it may have therapeutic value for the treatment of patients with chronic hepatitis.     

Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules.

The innate immune system recognizes microorganisms through a series of pattern recognition receptors that are highly conserved in evolution. Insects have a family of 12 peptidoglycan recognition proteins (PGRPs) that recognize peptidoglycan, a ubiquitous component of bacterial cell walls. We report cloning of three novel human PGRPs (PGRP-L, PGRP-Ialpha, and PGRP-Ibeta) that together with the previously cloned PGRP-S, define a new family of human pattern recognition molecules. PGRP-L, PGRP-Ialpha, and PGRP-Ibeta have 576, 341, and 373 amino acids coded by five, seven, and eight exons on chromosomes 19 and 1, and they all have two predicted transmembrane domains. All mammalian and insect PGRPs have at least three highly conserved C-terminal PGRP domains located either in the extracellular or in the cytoplasmic (or in both) portions of the molecules. PGRP-L is expressed in liver, PGRP-Ialpha and PGRP-Ibeta in esophagus (and to a lesser extent in tonsils and thymus), and PGRP-S in bone marrow (and to a lesser extent in neutrophils and fetal liver). All four human PGRPs bind peptidoglycan and Gram-positive bacteria. Thus, these PGRPs may play a role in recognition of bacteria in these organs.     

Conditional replication of duck hepatitis B virus in hepatoma cells

To facilitate investigations of replication and host cell interactions in the hepadnavirus system, we have developed cell lines permitting the conditional replication of duck hepatitis B virus (DHBV). With the help of this system, we devised conditions for core particle isolation that preserve replicase activity, which was not found in previous preparations. Investigations of the stability of viral DNA intermediates indicated that both encapsidated DNA and covalently closed circular DNA (cccDNA) were turned over independently of cell division. Moreover, we showed that alpha interferon reduced the accumulation of RNA-containing viral particles. The availability of a synchronized replication system will permit the biochemical analysis of individual steps of the viral replication cycle, including the mechanism and regulation of cccDNA formation.     

DNA of the hepatitis B virus in human generative cells

In spermatozoa of certain patients nucleotide sequences of hepatitis B virus were revealed in an integrated (chromosomal) and free states by means of dot- and blot-hybridization with a cloned HBV-probe. These observations support the conclusion made earlier on the lack of strict hepatotropism for HBV and, in addition, point to a possible involvement of HBV genomes in some molecular pathologies of men.     

Alpha interferon inhibits hepatitis C virus replication in primary human hepatocytes infected in vitro

Chronic hepatitis C is a common cause of liver disease, the complications of which include cirrhosis and hepatocellular carcinoma. Treatment of chronic hepatitis C is based on the use of alpha interferon (IFN-alpha). Recently, indirect evidence based on mathematical modeling of hepatitis C virus (HCV) dynamics during human IFN-alpha therapy suggested that the major initial effect of IFN-alpha is to block HCV virion production or release. Here, we used primary cultures of healthy, uninfected human hepatocytes to show that: (i) healthy human hepatocytes can be infected in vitro and support HCV genome replication, (ii) hepatocyte treatment with IFN-alpha results in expression of IFN-alpha-induced genes, and (iii) IFN-alpha inhibits HCV replication in infected human hepatocytes. These results show that IFN-alpha acts primarily through its nonspecific antiviral effects and suggest that primary cultures of human hepatocytes may provide a good model to study intrinsic HCV resistance to IFN-alpha.     

Chromosome remodeling related to hepatitis B virus replication in HepG2 cells

Hepatitis B Virus (HBV) covalently closed circular DNA (cccDNA) is the main replicative intermediate of HBV and is organized into minichromosomes by the interaction with histone and nonhistone proteins. The remodeling of HBV minichromosomes such as post-translational modifications of histone proteins plays an important role in regulating HBV replication. To determine whether other remodeling occurs in addition to acetylation of cccDNA-bound H3 histones in the presence of HBV replication, a cell culture replication model of HBV was used to assess the dynamic status of acetylation, phosphorylation, and methylation of cccDNA-bound H3 histones at various times after transient transfection of linear HBV DNA into human hepatoma, HepG2 cells. H3 histones bound to cccDNA were found to be phosphorylated, mono-methylated, and acetylated in HepG2 cells containing replicating HBV. The acetylation and methylation status of H3 histones bound to cccDNA paralleled HBV replication. Our results demonstrate that phosphorylation and methylation occur in the remodeling of HBV minichromosomes during HBV replication. The modifications of cccDNA-bound H3 histones were associated with the level of HBV replication. These findings suggest that alterations in the extent of minichromosome remodeling might be a potential target to inhibit HBV replication in the development of effective novel antiviral agents.     

Receptor-like cytoplasmic kinases are pivotal components in pattern recognition receptor-mediated signaling in plant immunity

Innate immunity is generally initiated with recognition of conserved pathogen-associated molecular patterns (PAMPs). PAMPs are perceived by pattern recognition receptors (PRRs), leading to activation of a series of immune responses, including the expression of defense genes, ROS production and activation of MAP kinase. Recent progress has indicated that receptor-like cytoplasmic kinases (RLCKs) are directly activated by ligand- activated PRRs and initiate pattern -triggered immunity (PTI) in both Arabidopsis and rice. To suppress PTI, pathogens inhibit the RLCKs by many types of effectors, including AvrAC, AvrPphB and Xoo1488. In this review, we summarize recent advances in RLCK-mediated PTI in plants.     

Ani immunomodulator Hepon inhibits hepatitis C virus replication in human cell cultures in vitro]

Antiviral activity of immunomodulator "Hepon" was evaluated in human cells culture infected with hepatitis C virus. "Hepon" presence protected human cells SW-13 from cytopathogenic effect of hepatitis C virus. Maximum antiviral effect was demonstrated by "Hepon" at concentration 1 mcg/mL. Control antiviral agent reaferon (interferon alfa-2a) was more potent as vitality protecting agent in the case of SW-13 human cells culture. "Hepon" activity is based on changes of cytokins and interferons spectrum so this immunomodulator is expected to be effective against different viruses including herpes virus and encephalocarditis virus.     

Respiratory epithelial cells in innate immunity to influenza virus infection

Infection by influenza virus leads to respiratory failure characterized by acute lung injury associated with alveolar edema, necrotizing bronchiolitis, and excessive bleeding. Severe reactions to infection that lead to hospitalizations and/or death are frequently attributed to an exuberant host response, with excessive inflammation and damage to the epithelial cells that mediate respiratory gas exchange. The respiratory mucosa serves as a physical and chemical barrier to infection, producing mucus and surfactants, anti-viral mediators, and inflammatory cytokines. The airway epithelial cell layer also serves as the first and overwhelmingly primary target for virus infection and growth. This review details immune events during influenza infection from the viewpoint of the epithelial cells, secretory host defense mechanisms, cell death, and recovery.