Human plasmacytoid dendritic cells (PDC) are key sentinels alerting both innate and adaptive immune responses through production of huge amounts of alpha/beta interferon (IFN). IFN induction in PDC isSuccessful defense against invading pathogens involves rapid recognition of conserved danger signals through members of the Toll-like receptor (TLR) protein family (1) and induction of cytokines that activate both innate and adaptive immunity. A principal effector integrating early antiviral and immunostimulatory activities is the alpha/beta interferon (IFN) system, including the group of IFN-␣ isotypes and IFN- (21). Although most types of cells can produce IFN through recognition of cytosolic double-stranded RNA (1a, 36, 44), or upon stimulation of TLR3 and TLR4 through double-stranded RNA or lipopolysaccharide, respectively (1), the vast amount of IFN upon entry of bacterial and viral pathogens is produced by a specialized cell population, plasmacytoid dendritic cells (PDC) (2, 6). Transcriptional induction of IFN genes is controlled by interferon regulatory factors (IRFs). IRF-3 mainly regulates IFN- induction, whereas IRF-7 has the ability to activate IFN-␣ promoters (22,25,45). In contrast to other cell types, PDC constitutively express high levels of IRF-7 such that expression of IFN-␣ by PDC is independent of the IFN-␣ receptor-mediated positive feedback via IFN- (3, 13, 16, 18), explaining in part the promptness of high-capacity IFN-␣ production.The TLR repertoire of human PDC is composed of TLR7 and TLR9, both located in the endosomal membrane. As shown recently, TLR7 and TLR8 recognize viral singlestranded RNA (8, 12) as well as imidazoquinolines such as imiquimod and resiquimod (R848) and guanosine analogs (reviewed in references 1 and 42). In contrast, TLR9 recognizes bacterial or viral DNA (1), including synthetic CpG oligodeoxynucleotides (ODN) (11). Indeed, recent work revealed IFN-␣ production in PDC after incubation with a variety of inactivated or live DNA and RNA viruses, including herpes simplex virus types 1 and 2 (16,19,23), murine cytomegalovirus (7), human immunodeficiency virus (46), influenza A virus (8,24), Sendai virus (14,16), and vesicular stomatitis virus (3,24). For herpes simplex virus (19,23), Influenza A virus (8,24), and vesicular stomatitis virus (24), the critical involvement of MyD88 adaptor-dependent TLR9 and TLR7 signaling has been demonstrated.In addition to perceiving external virus components through TLR7 and TLR9, human PDC have the means to sense cytosolic replicating RNA viruses. As we could show recently, respiratory syncytial virus (RSV) escapes from recognition by PDC TLRs (14). Nevertheless, infection with a particular laboratory strain of RSV (subtype A, strain Long), or cytosolic delivery of double-stranded RNA but not of poly(I:C) led to potent IFN-␣ induction in PDC in a TLR-and protein kinase R-independent manner (14).The considerable repertoire of tools for sensing pathogens combined with a tremendous capacity to produce IFN make human PDC the key sentinel...
Three subtypes of influenza A viruses, H1N1, H1N2 and H3N2, co-evolve in pigs in Europe. H1N2 viruses isolated from pigs in France and Italy since 1997 were closely related to the H1N2 viruses which emerged in the UK in 1994. In particular, the close relationship of the neuraminidases (NAs) of these viruses to the NA of a previous UK H3N2 swine virus indicated that they had not acquired the NA from H3N2 swine viruses circulating in continental Europe. Moreover, antigenic and genetic heterogeneity among the H1N2 viruses appeared to be due in part to multiple introductions of viruses from the UK. On the other hand, comparisons of internal gene sequences indicated genetic exchange between the H1N2 viruses and co-circulating H1N1 and/or H3N2 subtypes. Most genes of the earlier (1997-1998) H1N2 isolates were more closely related to those of a contemporary French H1N1 isolate, whereas the genes of later (1999-2000) isolates, including the HAs of some H1N2 viruses, were closely related to those of a distinct H1N1 antigenic variant which emerged in France in 1999. In contrast, an H3N2 virus isolated in France in 1999 was closely related antigenically and genetically to contemporary human A/Sydney/5/97-like viruses. These studies reveal interesting parallels between genetic and antigenic drift of H1N1 viruses in pig and human populations, and provide further examples of the contribution of genetic reassortment to the antigenic and genetic diversity of swine influenza viruses and the importance of the complement of internal genes in the evolution of epizootic strains.
Newcastle disease virus (NDV) is an intrinsically tumor-specific virus, which is currently under investigation as a clinical oncolytic agent. Several clinical trials have reported NDV to be a safe and effective agent for cancer therapy; however, there remains a clear need for improvement in therapeutic outcome. The endogenous NDV fusion (F) protein directs membrane fusion, which is required for virus entry and cell-cell fusion. Here, we report a novel NDV vector harboring an L289A mutation within the F gene, which resulted in enhanced fusion and cytotoxicity of hepatocellular carcinoma (HCC) cells in vitro, as compared with the rNDV/F3aa control virus. In vivo administration of the recombinant vector, termed rNDV/F3aa(L289A), via hepatic arterial infusion in immune-competent Buffalo rats bearing multifocal, orthotopic liver tumors resulted in tumor-specific syncytia formation and necrosis, with no evidence of toxicity to the neighboring hepatic parenchyma. Furthermore, the improved oncolysis conferred by the L289A mutation translated to significantly prolonged survival compared with control NDV. Taken together, rNDV/F(L289A) represents a safe, yet more effective vector than wild-type NDV for the treatment of HCC, making it an ideal candidate for clinical application in HCC patients.
The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). We have observed earlier that, in contrast to cultured human HCC cells, primary human hepatocytes (PHHs) are refractory to VSV infection. Impairment of the type I interferon (IFN) pathway in HCC cells has been suggested to be the mechanism by which these cells become susceptible to VSV infection. The goal of this study was to elucidate the nature of the IFN defect in human HCC. We demonstrate here that the defect in IFN-β signaling in HCC cells results from a deregulated IFN regulatory factor-3 (IRF3) pathway. Expression of IRF3-spliced variant (IRF3-nirs3) was constitutively observed in HCC cells and, importantly, also in primary HCC samples. In contrast, IRF3 was readily activated in PHHs after stimulation with dsRNA or infection with VSV. In addition, overexpression of IRF3-nirs3 significantly abrogated the IFN-β response to VSV infection and improved viral growth. Our data provide evidence that aberrant splicing of IRF3 in HCC contributes to the defect in IFN-mediated antiviral defenses. This work may provide a potential molecular basis for selecting HCC patients for oncolytic VSV therapy in future clinical trials.
Mucosal epithelia are invaded from the apical surface during a primary infection by herpes simplex virus type 1 (HSV-1). HSV-1 progeny virus, synthesized from latently infected peripheral neurons that innervate such epithelia, reinfects the epithelia most likely from the basolateral surface. The epithelial cell lines MDCK and Caco-2 can be induced in vitro to differentiate into polarized cells with distinct apical and plasma membrane domains separated by tight junctions if they are cultured on porous membrane filters. Our data using these culture systems showed that highly polarized epithelial cells were not susceptible to apical HSV-1 infection. However, HSV-1 infected these cells if added from the basolateral surface or if a depletion of extracellular Ca 2+ had weakened the strength of the cell-cell contacts. Basolateral infection and apical infection after the Ca 2+ switch required an intact microtubule network for genome targeting to the nucleus. This system can be used to identify the microtubule motors that HSV-1 uses during virus entry in polarized epithelial cells.
Multipotential mesenchymal stromal cells (MSC) are present as a rare subpopulation within any type of stroma in the body of higher animals. Prominently, MSC have been recognized to reside in perivascular locations, supposedly maintaining blood vessel integrity. During tissue damage and injury, MSC/pericytes become activated, evade from their perivascular niche and are thus assumed to support wound healing and tissue regeneration. In vitro MSC exhibit demonstrated capabilities to differentiate into a wide variety of tissue cell types. Hence, many MSC-based therapeutic approaches have been performed to address bone, cartilage, or heart regeneration. Furthermore, prominent studies showed efficacy of ex vivo expanded MSC to countervail graft-vs.-host-disease. Therefore, additional fields of application are presently conceived, in which MSC-based therapies potentially unfold beneficial effects, such as amelioration of non-healing conditions after tendon or spinal cord injury, as well as neuropathies. Working along these lines, MSC-based scientific research has been forged ahead to prominently occupy the clinical stage. Aging is to a great deal stochastic by nature bringing forth changes in an individual fashion. Yet, is aging of stem cells or/and their corresponding niche considered a determining factor for outcome and success of clinical therapies?
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