Viral nucleic acids often trigger an innate immune response in infected cells. Many viruses, including hepatitis C virus (HCV), have evolved mechanisms to evade intracellular recognition. ...Nevertheless, HCV-permissive cells can trigger a viral RNA-, TLR7-, and cell-contact-dependent compensatory interferon response in nonpermissive plasmacytoid dendritic cells (pDCs). Here we report that these events are mediated by transfer of HCV-RNA-containing exosomes from infected cells to pDCs. The exosomal viral RNA transfer is dependent on the endosomal sorting complex required for transport (ESCRT) machinery and on Annexin A2, an RNA-binding protein involved in membrane vesicle trafficking, and is suppressed by exosome release inhibitors. Further, purified concentrated HCV-RNA-containing exosomes are sufficient to activate pDCs. Thus, vesicular sequestration and exosomal export of viral RNA may serve both as a viral strategy to evade pathogen sensing within infected cells and as a host strategy to induce an unopposed innate response in replication-nonpermissive bystander cells.
► HCV RNA is selectively packaged within exosomes ► Exosomes carry viral PAMPs to neighboring pDCs ► Viral RNA-containing exosomes trigger IFN production by pDCs ► Cell-to-cell PAMP delivery is regulated by Annexin A2 and the ESCRT machinery
Due to the variable characteristics of renewable generation, batteries used in renewable-power systems can undergo many irregular, partial charge/discharge cycles. In turn, this can also have a ...detrimental effect on battery lifetime and can increase project costs. This study presents a method of improving battery lifetime in a small-scale remote-area wind-power system by the use of a battery/supercapacitor hybrid energy storage system. The supervisory control algorithm and hardware implementation are described and projected long-term benefits of the proposed system are assessed by simulation. A representative dynamic model of the overall system, incorporating realistic wind-speed and load-power variations has been developed. An analysis is presented of the potential improvement in battery lifetime that is achievable by diverting short-term charge/discharge cycles to a supercapacitor energy-storage system. This study introduces a method by which supercapacitor energy storage systems and control algorithms can be evaluated and implemented in the application area considered. The composition of a prototype test system is described and experimental results are presented to demonstrate system feasibility.
In this study, we show that replication-competent subgenomic hepatitis C virus (HCV) RNA can be transferred to permissive Huh7 cells, leading to the establishment of viral RNA replication. Further, ...we show that these events are mediated by exosomes rather than infectious virus particles. If similar events occur in vivo, this could represent a novel, albeit inefficient, mechanism of viral spread and immune escape.
Highlights • Hepatocellular HBV infection is noncytopathic. • HBV does not induce a measurable innate immune response in vivo. • Robust, broad adaptive immune responses mediate HBV clearance and ...acute hepatitis. • Weak, narrow adaptive responses mediate HBV persistence and chronic hepatitis. • Chronic hepatitis evolves to cirrhosis of the liver and hepatocellular carcinoma.
Hepatitis C virus (HCV) is a single-stranded RNA virus encoding a single polyprotein whose translation is driven by an internal ribosome entry site (IRES). HCV infection strongly induces antiviral ...interferon-stimulated gene (ISG) expression in the liver, yet it persists, suggesting that HCV can block ISG effector function. We now show that HCV infection triggers phosphorylation and activation of the RNA-dependent protein kinase PKR, which inhibits eukaryotic translation initiation factor eIF2 alpha and attenuates ISG protein expression despite normal ISG mRNA induction. ISG protein induction is restored and the antiviral effects of interferon are enhanced when PKR expression is suppressed in interferon-treated infected cells. Whereas host protein translation, including antiviral ISGs, is suppressed by activated PKR, HCV IRES-dependent translation is not. These results suggest that the ability of HCV to activate PKR may, paradoxically, be advantageous for the virus during an IFN response by preferentially suppressing the translation of ISGs.
Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the ...mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae. Hepatocellular antigen recognition triggers effector functions in a diapedesis-independent manner and is inhibited by the processes of sinusoidal defenestration and capillarization that characterize liver fibrosis. These findings reveal the dynamic behavior whereby CD8 TE control hepatotropic pathogens and suggest how liver fibrosis might reduce CD8 TE immune surveillance toward infected or transformed hepatocytes.
The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological ...basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Viruses and the autophagy machinery Dreux, Marlène; Chisari, Francis V.
Cell cycle (Georgetown, Tex.),
04/2010, Letnik:
9, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Autophagy is a major intracellular pathway for degradation and recycling of long-lived proteins and cytoplasmic organelles that plays an essential role in maintenance of homeostasis in response to ...starvation and other cellular stresses. Autophagy is also important for a variety of other processes including restriction of intracellular pathogen replication. Our understanding of the fascinating relationship between viruses and the autophagy machinery is still in its infancy but it is clear that autophagy is a newly recognized facet of innate and adaptive immunity against viral infection. Although the autophagy pathway is emerging as a component of host defense, certain viruses have developed strategies to counteract these antiviral mechanisms, and others appear to have co-opted the autophagy machinery as proviral host factors favoring viral replication. The complex interplay between autophagy and viral infection will be discussed in this review.
In addition to its cellular homeostasis function, autophagy is emerging as a central component of antimicrobial host defense against diverse infections. To counteract this mechanism, many pathogens ...have evolved to evade, subvert, or exploit autophagy. Here, we report that autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12) are proviral factors required for translation of incoming hepatitis C virus (HCV) RNA and, thereby, for initiation of HCV replication, but they are not required once infection is established. These results illustrate a previously unappreciated role for autophagy in the establishment of a viral infection and they suggest that different host factors regulate the translation of incoming viral genome and translation of progeny HCV RNA once replication is established.
Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, ...cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhosis and hepatocellular carcinoma.
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