Die Rolle des Interferon Systems bei der Hepatitis-C Virus Replikation

The Hepatitis-C virus is the leading cause of chronic hepatitis. The host immune system identifies specific viral patterns, and induces an Interferon (IFN) response. IFNs are known to suppress HCV replication in vitro, by the induction of antiviral responses mediated by Interferon stimulated genes (ISGs) and the current treatment regimen of IFN-α and Ribavirin has proven partly successful.However, HCV remains a poor inducer of interferon. This feature is attributed to the ability of the HCV proteins to cleave or successfully circumvent most proteins involved in the interferon pathway. IFN-independent antiviral mechanisms have been shown to exist as bypass mechanisms in the event of viral evasion of the IFN system. In this study, gene knock-out lines lacking key molecules involved in induction, reaction and amplification of type I IFNs as well as antiviral responses induced by alternative pathways was used to determine the role of the type I IFN system in the restriction of HCV replication. The data provided here indicate the novel antiviral functions of Interferon regulatory factors (IRFs) and interferon stimulated genes (ISGs) in limiting HCV replication in mouse cells. Mouse cells with a competent interferon signalling system did not permit replication of HCV whereas cells with individual defects in the type I interferon response, IRF-3, STAT-1 and the ISG PKR permitted detectable levels of replication. However, replication was observed in cells with defective IRF-5, IRF-7 and IRF-1 only in the absence of a type I interferon response. These results argue, that lesion of these genes weaken such IFN-independent defences to the extent that HCV replication is detectable upon neutralization of secreted IFN. Therefore, we conclude that in WT MEFs, IFN-dependent and independent mechanisms contribute to the control of HCV replication, and that IFN-independent defences are mediated through IRF-5,IRF-7, IRF-1 and PKR. This is compatible with the current view that these factors are essential for the IFN-mediated antiviral activity. Taken together, these data show that apart from the predominant type I IFN response, IFN-independent antiviral effects are involved in restricting HCV replication in mouse fibroblasts. Similarly, data from primary mouse hepatocytes indicate that in addition to the type I IFN responses; other interferons such as type III interferon may also exert antiviral effects.Das Hepatitis-C-Virus ist eine der häufigsten Ursachen chronischer Hepatitis. Bei viralen Infektionen erkennt das Immunsystem spezifische virale Strukturen und induziert daraufhin eine Interferon (IFN)-Antwort. IFNs sind dafür bekannt, die HCV-Replikation in vitro durch die Induktion Interferon stimulierter Gene (ISGs) mit antiviralem Effekt, zu unterdrücken. Deshalb besteht die verbreitete Therapie von Hepatitis C in der Behandlung mit pegylierten Interferon α in Kombination mit dem Nukleosidanalogon Ribavirin. Allerdings produzieren HCV-infizierte Zellen nur geringe Mengen IFN, da viele HCV-Proteine die Fähigkeit besitzen Proteine des IFN Signalweges zu blocken oder ihrer Wirkung zu entgehen. Es konnte gezeigt werden, dass es IFN-unabhängige antivirale Mechanismen gibt, welche die Aufgabe von IFN übernehmen, wenn deren Wirkung von Viren umgangen wird. In dieser Studie wurden murine embryonale Fibroblasten mit einem Defekt in der Induktion, Amplifikation und Reaktion vom Typ I IFNs sowie deren antiviralen Wirkung verwendet, um die Rolle des Typ I IFN-System in der Inhibition der HCV-Replikation zu bestimmen. Die hier dargestellten Daten zeigen eine neue antivirale Funktion Interferon regulierender Faktoren (IRF) und Interferon stimulierter Gene (ISGs) die Replikation von HCV in murinen Zellen zu hemmen. HCV ist nicht in der Lage in Mauszellen mit einem intakten Interferon-System zu replizieren. Zellen mit einem Defekt im IRF-3-, STAT-1- und PKR-Gen erlauben eine Replikation des Virus. Jedoch wurde Replikation in IRF-5-, IRF-7- und IRF-1 defizienten Zellen nur in Abwesenheit eines Typ I Interferon-Antwort beobachtet. Diese Ergebnisse zeigen, dass der Verlust dieser Gene die IFN-unabhängigen Abwehrmechanismen schwächen, was die Replikation von HCV ermöglicht. Daraus schließen wir, dass in WT MEFs, IFN-abhängige und -unabhängige Mechanismen zur Steuerung der HCV-Replikation beitragen und das IFN-unabhängigen Abwehrmechanismen durch IRF-5, IRF-7, IRF-1 und PKR vermittelt werden. Dies stützt die verbreitete Meinung, dass diese Faktoren essentiell für die IFN-vermittelten antiviralen Aktivität sind. Zusammengenommen zeigen diese Daten, dass abgesehen von der dominanten Wirkung von Typ I IFN, IFN-unabhängige antivirale Effekte an der Restriktion der HCV-Replikation in Mausfibroblasten beteiligt sind. Experimente in murinen Hepatozyten lassen weiterhin vermuten, dass neben Typ I IFN auch andere Interfone, wie Typ III IFN antiviralen Effekt vermitteln können

A RECENT UPDATE ON HISTOGENESIS OF ADENOMATOID ODONTOGENIC TUMOR: A REVIEW

Adenomatoid odontogenic tumor (AOT) is a relatively rare benign, epithelial tumor of odontogenic origin. There is varying class of thoughts contemplating this lesion to be a hamartoma or neoplastic growth of odontogenic epithelium. Controversy regarding the histogenesis of the lesion is plentiful in earlier literature. The recent advent of immunohistochemical and ultrastructural studies has aided in throwing light on the tissue of origin of this tumor. This review aims at understanding the evolving concepts of histogenesis of AOT to better understand the biological behavior of the lesion. The review of AOT was carried out using PubMed and Google Scholar databases and 39 articles from the year 2001 to 2016 which contributed to the histogenesis of AOT were included for review. Since the origin of the cystic lining is similar to a reduced enamel epithelium and not the dental lamina, we propose the former to be the progenitor of AOT. Furthermore, we consider extra-follicular, as well as peripheral AOTs, originate from the remnants of Hertwig’s epithelial root sheath (epithelial rests of Malassez), which complies with the common histology for all these variants

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types

Influence of reduced graphene oxide on flow behaviour, glass transition temperature and secondary crystallinity of plasticized poly(vinyl chloride)

International audienc

Influence of reduced graphene oxide on flow behaviour, glass transition temperature and secondary crystallinity of plasticized poly(vinyl chloride)

International audienc

Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.

Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication

Utility of saliva and hair follicles in donor selection for hematopoietic stem cell transplantation and chimerism monitoring

Selection of an HLA identical donor is a critical pre-requisite for successful hematopoietic stem cell transplantation (HSCT). Most transplant centers utilize blood as the most common source of DNA for HLA testing. However, obtaining blood through phlebotomy is often challenging in patients with conditions like severe leucopenia or hemophilia, pediatric and elderly patients. We have used a simple in-house protocol and shown that HLA genotypes obtained on DNA extracted from saliva or hair are concordant with blood and hence can be used for selection of donors for HSCT or organ transplantation. Similarly, for post-HSCT chimerism monitoring, non-availability of pre-transplant DNA samples poses a major limitation of reference STR fingerprints. This study shows that DNA obtained post-HSCT from hair follicles can be used to generate pre-transplant patient specific fingerprints while the STR profiles obtained in saliva samples cannot as these display a mixed state of chimerism

Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular Gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here, we report that Listeria DNA is sorted into extracellular vesicles (EVs) in infected cells and delivered to bystander cells to stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TANK-binding kinase 1 phosphorylation, which is essential for the sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T-cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair antibacterial defence